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The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations around the World, Secular Trends, and Changes after Migration

Division of Ambulatory Pediatrics and Adolescent Medicine (A.-S.P., J.-P.B.), University of Liège, B-4000 Liège, Belgium; Department of Growth and Reproduction (G.T., A.J., N.E.S.), Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen Ø, Denmark; and Departments of Paediatrics and Physiology (J.T.), University of Turku, 20520 Turku, Finland

Correspondence: Address all correspondence and requests for reprints to: Jean-Pierre Bourguignon, M.D., Ph.D., Division of Ambulatory Pediatrics and Adolescent Medicine, University of Liège, Centre Hospitalier Universitaire Sart Tilman, B-4000 Liège, Belgium. E-mail: jpbourguignon{at}ulg.ac.be

	Abstract

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 
During the past decade, possible advancement in timing of puberty has been reported in the United States. In addition, early pubertal development and an increased incidence of sexual precocity have been noticed in children, primarily girls, migrating for foreign adoption in several Western European countries. These observations are raising the issues of current differences and secular trends in timing of puberty in relation to ethnic, geographical, and socioeconomic background. None of these factors provide an unequivocal explanation for the earlier onset of puberty seen in the United States. In the formerly deprived migrating children, refeeding and catch-up growth may prime maturation. However, precocious puberty is seen also in some nondeprived migrating children. Attention has been paid to the changing milieu after migration, and recently, the possible role of endocrine- disrupting chemicals from the environment has been considered. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes.

I. Introduction

II. Normal Puberty and Variations in Timing

A. Clinical indicators

B. Age references in well-off conditions

C. Age references in underprivileged conditions

D. Secular trends

III. Precocious Puberty

A. Age limits

B. Common etiologies

C. Children migrating from developing countries

IV. Possible Mechanisms of Variations in Timing of Puberty around the World and after Migration

A. Genetic factors (family, ethnicity, gender)

B. Intrauterine conditions

C. Nutrition

D. Other stresses

E. Light-darkness cycle and climatic conditions

F. Exposure to endocrine-disrupting chemicals (EDCs)

V. Conclusion and Future Research Directions

	I. Introduction

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 
PUBERTY RESULTS FROM the awakening of a complex neuroendocrine machinery in which the primary mechanism is still unclear (1). A peculiarity of sexual maturation in the human species is the 4- to 5-yr physiological variation in age at onset of puberty that is observed among normal individuals despite relatively similar life conditions (2). This variability involves genetic factors, as indicated by the studies on heritability of menarcheal age (3), although the molecular determinants are yet to be identified. Other factors such as ethnicity, nutritional conditions, and secular trends have been shown to influence the physiological range in age at the onset of puberty (4, 5). In these conditions, the age limits used to define sexual precocity are necessarily subject to local assessment and regular revision. Whereas reference data seemed to have stabilized in most industrialized countries during the 1990s, two recent American studies (6, 7), which were reviewed by Lee et al. (8), highlighted an unexpected and unexplained advance in physiological age at the onset of breast development. These findings urged us to examine the current variations in timing of puberty around the world and the related age limits for sexual precocity. In addition, new aspects regarding the etiology of sexual precocity provided another reason to consider the differences in timing of puberty worldwide. Most patients with sexual precocity are diagnosed as idiopathic, and no causative process is found at brain imaging (9, 10). Recently, a special form of sexual precocity has been described in foreign children adopted from developing countries to Western Europe. The occurrence of early or precocious sexual maturation in such a unique situation of changing environment was originally described in Indian girls adopted in Sweden (11). Subsequently, similar observations were made in several European countries and involved children from various countries (12, 13, 14, 15, 16, 17, 18).

The aim of this review is to address the significance of early onset of puberty in children living in their home countries or migrating to other countries. Emphasis will be put on the differences in age limits for pubertal development between countries and ethnic groups. The possible etiologies for advancement in timing of puberty in some conditions will be discussed in the light of our current understanding of the mechanism of the onset of puberty.

	II. Normal Puberty and Variations in Timing

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 
A. Clinical indicators
Although the concerns about sexual precocity and changes in timing of puberty appear to be much greater in girls than in boys, these issues must be addressed in both sexes, in a comprehensive and comparative perspective. In boys, the first sign of pubertal development is an increase in testicular volume above 3 ml, consistent with Tanner G2 stage (2, 9). This change, however, can be observed only by thorough evaluation at physical examination (2, 19). There is no reliable event that can be recalled to time male pubertal development when taking a medical history. In girls, the earliest manifestation of puberty is acceleration in growth velocity, which, however, is difficult to ascertain because it requires several accurate height measurements each year (20). The commonly used markers of the timing of female puberty are thelarche and menarche, of which different characteristics are summarized in Table 1. Thelarche is the first appearance of breast development defined as Tanner B2 stage (2). This relatively obvious pubertal sign might not be easily distinguished from fat tissue in slightly obese girls. Importantly, the appearance of pubic hair is dependent primarily on testicular androgens in boys and on adrenal androgens in girls. The developmental increase in adrenal androgen secretion is referred to as adrenarche and occurs independently of the pituitary- gonadal maturation or gonadarche (8, 21, 22). Thus, development of pubic hair in girls does not provide any information on pituitary-ovarian maturation. The evaluation of Tanner stages can be obtained by self-assessment or physician’s assessment. The self-assessment of pubertal characteristics has been shown to be nonreliable (23), although the answers of adolescents to a global question on development compared with their peers can be a valid approach (24). The assessment of Tanner stages by professionals provides more reliable information than self-assessment but involves significant variations between observers (23). The Tanner stages provide semiquantitative information with less accuracy than using the menarcheal age to assess the timing of pubertal development.

In the published literature on the timing of puberty, the data are given either as mean ± SD in some studies, assuming that the data are normally distributed, or as median and centiles in other studies. This issue is important because the mean and median are comparable only when the distribution of data is Gaussian (Fig. 1A). This can be the case in a well-off setting, as indicated by the symmetrical distribution of centiles of menarcheal age in North American girls (31). By contrast, an asymmetrical distribution of data with increased variability toward late ages (Fig. 1B) can be observed in an underprivileged setting (32). In these conditions, the calculated mean age will be greater than the median. An increased prevalence of early sexual maturation in a population such as migrating children can result from either a subset of fast maturers causing an asymmetrical distribution of ages at onset of puberty (Fig. 1C) or a shift of the whole population toward earlier timing of puberty (Fig. 1D), or both. The magnitude of the SD provides an index of variability in timing of puberty. For instance, during the 19th century (33), not only was the average menarcheal age later but also the SD was greater than today (Fig. 1E).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Schematic representation of the distribution of timing of puberty (e.g., menarcheal age) in different conditions. The important parameters are the median and mean ages, the symmetry or asymmetry of distribution, and the variability as expressed by the SD values (–2 SD to +2 SD illustrated).

B. Age references in well-off conditions
In the United States, Mac Mahon (35) reported a mean menarcheal age of 12.8 yr in 1973. Very similar data (12.7 yr) were reported by Tanner and Davies (31) in 1985 with a median age of 10.9 yr for onset of breast development. This is very close to the data obtained in most European countries (Fig. 2). In 1997, however, a publication from the American Academy of Pediatrics-Pediatric Research in Office Settings (PROS) network reporting on more than 17,000 girls led to an adjustment in the above-mentioned limits in the United States (6). These authors found the mean age at B2 to be 10.0 yr in White American girls and 8.9 yr in African-American girls, with –2 SD limits of 6.3 and 5.0 yr, respectively. These findings generated comments on the possible overestimation of breast development because assessment was made through visual inspection only, whereas palpation may be required to distinguish between adipose and glandular tissue (8, 36). In addition, the data were not corrected for the difference in racial representation that resulted from only 10% of the participants in the PROS study being African-Americans (37). This, together with other possible biases such as the increased variance due to the involvement of multiple observers, raises the issue of whether or not the onset of puberty is shifted toward earlier ages in the United States (36, 37). In another large cross-sectional American study (the National Health and Nutrition Examination Survey, NHANES III), a similarly early median age of 9.7 yr at B2 was found in White Americans (7), although slightly less advanced median ages of 10.4 yr (White Americans) and 9.5 yr (Black Americans) were recently reported in subgroups from that cohort (38). The large NHANES III study, however, was not different from the PROS study in that it was cross-sectional and involved many different observers, without mention of the possible or systematic use of palpation to assess breast tissue development. Therefore, confirmation of those findings may warrant a carefully designed prospective longitudinal study involving a limited number of observers who use breast palpation to assess development. Interestingly, the mean menarcheal age found in the PROS study (6) did not show the same shift as age at the onset of breast development because age at menarche (12.9 yr in White Americans and 12.7 yr in Black Americans) was unchanged when compared with the data reported earlier (31, 35). Here also, a bias was possible in the PROS study where the subjects were aged 12 yr or less and mean menarcheal age was extrapolated by probit analysis. However, in the NHANES III study (7), which involved subjects aged up to 17 yr, menarche occurred in White Americans at an age (12.5 yr) similar to that extrapolated in the PROS study. The similar menarcheal ages observed in the United States recently (6, 7) and several decades earlier (31, 35) suggest that the secular trend toward earlier menarche has stopped. This issue was more specifically addressed in two recent studies based on the NHANES III data and the National Health Examination Survey (NHES) data (39, 40 ). In these two studies, the median menarcheal age in the U.S. girls studied around 1990 was 12.43 or 12.54 yr with a reduction of 0.34 yr in 30 yr or 0.21 yr in 25 yr, respectively. These differences are much less than that described for breast development in the same period. Is it possible that the secular trend toward earlier menarche has been underestimated in the two large cross-sectional American studies (6, 7)? Such a possibility might be consistent with the data from the Bogalusa Heart study, which reported on a smaller biracial cohort of 1082 girls studied in 1992–1994 (41). In this study, the mean menarcheal age was found to be 11.4 and 11.5 yr in African-American and White-American girls, respectively, which is much earlier than in the PROS and NHANES studies and indicates an important secular trend, because in 1978–1979, the menarcheal age was 12.3 and 12.2 yr, respectively, in the same area (41). Several factors might account for this discrepant observation. First, local environmental changes in the semirural area of Bogalusa may be greater than in the United States in general, resulting in faster increase in body fatness. Between 1974 and 1994, the prevalence of body mass index (BMI) greater than the 85th percentile among 5- to 14-yr-old subjects has increased by 22% (from 15 to 37%) in the Bogalusa study (42). This race- and gender-independent increase is much more than the 7% increase found using the same criteria in the NHES study between 1963 and 1991 in 6- to 17-yr-old subjects (43) and the 8% increase found in the adult U.S. population (44). Another bias in the report from the Bogalusa cohort (42) was that two different cohorts of subjects were studied at a 15-yr interval. The impact of such a biasing factor is likely because a recent analysis including a longitudinal subset of 2058 subjects showed that the median menarcheal age in the Bogalusa cohort was 12.6 yr in White Americans and 12.3 yr in Black Americans, with a secular reduction of 0.8 and 0.17 yr during the past 20 yr, respectively (45). In a recent longitudinal study of an equal proportion of White and Black Californian girls, similar mean menarcheal ages of 12.7 and 12.0 yr, respectively, were reported (46). In a cross-sectional study performed in the 1970s and involving 84% of White American girls, the mean menarcheal age was 12.2 yr (47). Thus, it is likely that the average menarcheal age has almost stabilized in the United States, whereas age at onset of breast development may have declined. As already mentioned, the increasing difference between trends in ages at B2 and menarche might involve an inverse correlation between age at onset of puberty and duration of puberty (28, 29, 30). However, a trend toward increasing time length between B2 and menarche is somewhat contradictory to the observation of a secular acceleration of the progression or tempo of pubertal development in Dutch and Swedish boys and girls (48). Alternatively, unidentified external factors might cause breast development to start earlier without affecting menarcheal age.

View larger version (32K): [in this window] [in a new window]   FIG. 2. Average (mean or median) ages at onset of breast development (B2) or menarche in different well-off populations around the world. The most recently published data were used to provide an update.

In the pioneering work of Marshall and Tanner (19), which provided age references for male pubertal development in 1970, the mean age for G2 stage was found to be 11.6 yr in the United Kingdom. Very similar data have been reported for the United States (11.5 yr) in 1985, Sweden (11.6 yr) in 1996, The Netherlands (11.5 yr) in 2001, and Switzerland (11.2 yr) in 1983 (31, 51, 57, 74). In a longitudinal Spanish study, the mean age at G2 was 12.3 yr (63). These stabilized references are in contrast to the lowered median age of 9.7 yr at G2 that has been reported from the American NHANES III study, which was performed in the period 1988–1994 (75). This study involved 25% of White Americans, 37% of Mexican Americans and 38% of African Americans with respective median ages at G2 of 10.1, 10.4, and 9.5 yr, a difference that was not significant (72). In a more recent subgroup study from the same cohort, similar ages were reported (38). Those data were obtained based on visual inspection without palpation of testicular volume or assessment of testicular size. As mentioned in an editorial comment by Reiter and Lee (76), that bias may be important because the increase in testicular volume or size is critical in the evaluation of the G2 stage of Tanner. The inaccuracy of visual assessment might also account for the one-stage variance between physicians involved in the study (76) and the surprisingly long time interval of 2 yr between G2 and P2 stages (75), whereas this interval was found to be 1 yr by others (51, 59). There are unfortunately no data available from comparable studies. In the NHES study, G2 data were not available (77). In a longitudinal study of 78 boys, Roche et al. (78) reported a mean age of 11.3 yr at G2, but the validity of these data may be limited because of self-assessment. Biro et al. (79) also performed a longitudinal study, but they used modified global stages of puberty that are not comparable. Thus, it is difficult to draw conclusions before we have additional data from a prospective study with assessment of testicular volume or size. The stable mean age at G5 (15.3 yr) in the NHANES III study is in contrast with the earlier age at G2. This would suggest that the tempo of male puberty is, in fact, decreasing. In some countries such as Hong Kong where the median ages at G2 and B2 are 11.4 and 9.8 yr, respectively (66, 80), the age at G2 in boys has not changed, whereas the age at B2 is declining. Although girls classically precede boys by an average of 0.8 yr for the onset of puberty (51, 53, 57), such a sexual dimorphism has not been found any longer in two recent American and German studies where identical ages at B2 and G2 were reported (6, 55, 75, 81). Such discrepancies point to the need to compare studies conducted using similar design and methods in different countries.

C. Age references in underprivileged conditions
In developing countries, inequalities related to socioeconomic status or life setting (urban vs. rural) are still prominent and might account for important variations in timing of puberty within and among countries (5, 65). Secular trends can still be observed in developing countries because of current changes in living standards. When subgroups of girls in well-off and underprivileged conditions are compared in some countries (Fig. 3), the impact of these differences in living standards is obvious (5, 68, 72, 73, 82, 83). The socioeconomic status of the study group is not always specified, and we can then assume an average living standard. In recent reports from Nigeria, Guatemala, or Colombia (32, 84, 85), later ages at menarche were observed compared with well-off girls from the neighboring countries of Chile and Venezuela (70, 71). In countries such as China and Senegal where girls living in underprivileged conditions have been studied, the mean menarcheal age is as great as 16.1 yr (86, 87). The variability in menarcheal age can be translated into the coefficient of variation (CV), which is the SD expressed as a percentage of the mean. The CV is greater in underprivileged girls from Cameroon (11.6%) than in privileged girls from the same country (8.2%) (72), although such a difference is not observed in South Africa (73). A low CV (9.2–10.0%) is obtained in other well-off conditions (6, 64, 69). Taken together, these data highlight the crucial role of socioeconomic and nutritional conditions in the timing of puberty. A similar conclusion was drawn in a recent study reviewing menarcheal age in 67 countries (88). These authors pointed out that, on a large scale, extrinsic factors were crucial: the effects of early involvement in physical activities on energy expenditure were emphasized in relation to frequent illiteracy rate.

View larger version (16K): [in this window] [in a new window]   FIG. 3. Average (mean or median) menarcheal age in different developing countries. The data are shown separately for different living conditions.

View larger version (22K): [in this window] [in a new window]   FIG. 4. Secular trend in menarcheal age in different countries around the world. A, Twin set of average data obtained after 1960 in different countries at several 10-yr intervals. B, Secular difference in menarcheal age calculated from those data. For the purpose of comparison, the average secular trend observed before 1960 in the United States and in Europe is also shown.

The variability in menarcheal age in France as reflected by the CV was greater in the mid-19th century (17.3%) than in the mid-20th century (10.0%) (33, 60). It appears, however, that between the 1930s and the 1960s in the United States, CV was 9–10% and did not change any longer, whereas the decline in average menarcheal age was still progressing (89). In China, where the secular trend in decline of menarcheal age was still important between the early 1970s and the early 1990s (Fig. 4), there was only a modest concomitant reduction in that CV from 11.9 to 9.8% (87). Such a dissociation between the mild changes in variability of age at menarche and the steady decline in average menarcheal age suggests that both parameters are influenced by different factors or differently by the same factors.

Some authors have looked into the secular trend dynamics using other markers such as the onset of breast development in girls and genital development in boys. In Sweden and the United Kingdom, the onset of breast development has been found to be slightly earlier in 1980 than in the 1960s or 1970s (48). In Denmark (97), the average age at onset of breast development even tended to increase between 1964 (10.6 yr) and 1990–1991 (11.2 yr). In Europe, there is no evidence of marked secular reduction in average age at B2 such as shown in the United States (6, 7). The age at G2 has shown some increase in The Netherlands during the last decades, whereas a decrease has been observed in Sweden (48). Although a methodological bias is possible due to the small number of boys in the G2 stage, such discrepant observations might point to some country-specific environmental changes. These observations are also raising important issues regarding the significance of the data in relation to the markers used to evaluate the timing of pubertal development as discussed above.

	III. Precocious Puberty

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 
A. Age limits
On the basis of the above mentioned average ages at onset of pubertal development and assuming a Gaussian distribution in the normal population, abnormally precocious sexual development has been defined in Europe as less than 8 yr for the B2 stage in girls and less than 9 yr for the G2 stage in boys (10, 98, 99). These age limits, which are above the 99th centile, have been used for several decades and are still used currently. Similar age limits were thought to be relevant to the United States until the publication of the PROS study (6) prompted Kaplowitz and Oberfield (100) to recommend, on behalf of the Lawson Wilkins Pediatric Endocrine Society, to reset the age limit for nonphysiological onset of breast development at 7 yr in Caucasian girls and 6 in African-Americans. Some American colleagues, however, did not share the opinion of Kaplowitz and Oberfield and advocated a possible recruitment bias through pediatricians’ offices (36). In addition, the unexplained dissociation between earlier breast development and relatively unchanged menarcheal age was raising indirectly the issue of the reality of breast development estimated through visual inspection. The definition of appropriate age limits is crucial to restrict diagnostic evaluation and possible therapeutic intervention to children with abnormal precocious development (98, 99). In a recent review of 223 patients referred for sexual precocity occurring between 7 and 8 yr in white girls or 6 and 8 yr in black girls, Midyett et al. (101) found that 47% showed both breast and pubic hair development, 35% had bone age at more than 3 SD above chronological age, and 12% appeared to have a nonidiopathic form of sexual precocity. The authors concluded that occurrence of sex characteristics between 6 and 8 yr is not necessarily benign and may warrant diagnostic and therapeutic intervention (101). Thus, the question of age limit for sexual precocity does not have any definitive and unequivocal answer.

B. Common etiologies
Sexual precocity is classified as central, gonadotropin-dependent, i.e., driven by the central nervous system, when it results primarily from early hypothalamic-pituitary maturation (8, 99). Central precocious puberty represents four fifths of the total number of patients with precocious puberty (99, 102) and is much more frequently seen in girls than in boys. Idiopathic central precocious puberty is diagnosed when early pubertal development (including acceleration of growth and bone maturation) is associated with a pubertal pattern of gonadotropin secretion (increased LH secretion) and when there is no evidence of organic cause provided through history, physical examination, or brain imaging (9, 98). Among patients with central precocious puberty, the proportion of idiopathic forms varies between 58 and 96%, as reviewed recently (103, 104). This proportion is greater in girls than in boys, who show a higher prevalence of recognizable organic forms. As shown in Fig. 5, the female to male ratio found among the patients with central precocious puberty in the studies published between 1961 and 1990 was relatively similar, around 3:1 to 4:1 (102, 105, 106, 107, 108, 109, 110, 111, 112). In the same studies, the idiopathic to organic ratio was around 2:1, indicating that two thirds of the patients had idiopathic forms and one third had organic forms with identified neurogenic etiologies. In more recently published studies from four European countries as well as from the United States (10, 17, 18, 113, 114, 115), the proportion of female patients and idiopathic forms has clearly increased (Fig. 5). In a recently published American series, however, the sex ratio and etiological distribution were similar to the data from early studies despite the changing age limits for sexual precocity in the United States (116). It should be noted that this study reported on final height and involved patients diagnosed several years earlier and referred to the NIH with possible recruitment biases. The changing gender and etiological distribution of patients with precocious puberty in the United States could have resulted from the recently observed reduction in age at onset of puberty, before the age limits for sexual precocity were revised. Such an explanation, however, is unlikely in Europe where the physiological age at onset of puberty and the age limits for sexual precocity did not change during the past decade. An increased variability in timing of puberty without change in the mean ages could account for an increasing number of girls with idiopathic forms. Based on the diagnostic advances made during the past decades using nuclear magnetic resonance imaging, an increasing proportion of idiopathic forms would not have been expected. Another clue to the changing epidemiology of central precocious puberty could be the occurrence of new etiologies as suggested by the increasing proportion of migrating children who develop sexual precocity, as discussed below.

View larger version (33K): [in this window] [in a new window]   FIG. 5. Gender and etiological distribution of patients with central precocious puberty in the series published between 1961 and 2001 in relation to the year of publication and the country of study (DK, Denmark; F, France; UK, United Kingdom; NL, the Netherlands; B, Belgium). The number of patients and reference (in parentheses) are indicated at the top of each bar.

C. Children migrating from developing countries
After an initial report from Sweden in 1981 (118), sexual precocity has been reported in children migrating from developing countries to different European countries, primarily through international adoption (11, 12, 13, 14, 15, 16, 17, 18). So far, there is only one similar report from the United States published in abstract form (119). Some data from the published series are summarized in Table 2, and methodological aspects are listed in Table 3. In the original Swedish report and the subsequent Dutch, French, and American reports, cohorts of foreign adopted patients were studied, and the mean menarcheal age was evaluated through questionnaires sent out to the families (11, 13, 16, 119). In these studies, the absolute frequency of sexual precocity was undoubtedly increased (Table 3) but was variable among the studies between 13% (11) and 30% (119). In the Swedish cohort study, the menarcheal ages, although advanced, followed a relatively symmetrical pattern of distribution (11), such as expected in normal adolescents (120). This indicates that advanced puberty was a general feature of the whole cohort (Fig. 1D) instead of precocity being a feature of a particular subset (Fig. 1C). It is of note that the variability in menarcheal age (CV, 11.5–24.7%) in these cohorts (13, 16, 119) can be greater than in the nonmigrating girls living in well-off conditions. Several biases may have influenced the calculation of the frequency of sexual precocity. In the cohort studies, sexual precocity was defined as early menarche, which was reported in the questionnaire (11, 13, 16). Such a definition was different from the patient studies in which early breast development was the first criterion used to define precocity (14, 16, 17, 18). This distinction is important because thelarche and menarche may have a different significance (Table 1). India was the only country of origin in the Swedish study (11), whereas several different countries were involved in the other studies (13, 16, 119). The differences in country of origin were unlikely to bias the findings because, in three cohort studies, the average menarcheal age was advanced in comparison with data from the foster country and the country of origin as well (11, 13, 16). In the study by Oostdijk et al. (13), mean ages at menarche differed significantly, with the lowest observed in girls from India (11.2 yr) and the highest in girls adopted from South Korea (12.4 yr). In the Swedish study, birth date was uncertain in 28% of subjects, but similar data were obtained when the subsets with certain and uncertain birth date were compared (11). In a study on children adopted from China, 11% were thought to have an inaccurate birth date (121). Birth date uncertainty is a potential bias in all the studies, with possible differences among the countries of origin. This, however, is unlikely to account for false diagnosis of sexual precocity in most migrating children, although such a possibility should be kept in mind for individual patients. More important, the bias of parental concern about early sexual development of their adopted child may have influenced the decision to respond to the questionnaire, accounting for overrepresentation of early maturers in the responding families.

In the foreign children with sexual precocity, evidence of early hypothalamic-pituitary maturation and normal brain imaging has been provided, leading to the diagnosis of idiopathic central precocious puberty (14, 16, 17). In all the studies, sexual precocity was seen much more frequently in foreign girls than in boys (11, 12, 13, 14, 16, 17, 119). Such a sexual dimorphism might reflect the general and unexplained female preponderance of idiopathic central precocious puberty. However, a precise cause influencing specifically the female endocrine system cannot yet be excluded. The early hypotheses to explain sexual precocity in foreign adopted children after migration have incriminated the transition from an underprivileged to a privileged environment (11, 12). A new perspective has come from the recent Belgian report indicating that 12 patients from a total group of 145 were foreign children moving together with their original families without past history of deprivation (17). The observation of both nonadopted and adopted foreign children among the patients with precocious puberty was also found in Denmark (Table 2). The occurrence of precocious puberty in nonadopted migrating children suggests the possible role of factors related to migration and change of environment. Although the impact of former nutritional and emotional stress is less likely in children moving together with their original families, it is possible as well that such children are relieved from some stressful conditions after leaving their country.

The available data on actual or predicted adult height in migrating girls, including those with early or advanced puberty (11, 13, 14, 17), indicate that the average final height was close to or below the third centile of national references in the foster countries (Table 2). The interpretation of height data is difficult because of the possible role of ethnic differences, unknown short parental height, and intrauterine growth retardation (IUGR) in addition to precocious puberty. The observation of short adult stature prompted several clinicians to study the effects of combined GnRH agonist suppression of puberty and stimulation of growth with GH (125, 126). Pubertal growth and final height are obviously very important factors in relation to changes in pubertal timing and secular trends in the general population as well as in migrating children. These aspects, however, involve many factors beyond the control of pubertal timing and will not be discussed in the present paper.

	IV. Possible Mechanisms of Variations in Timing of Puberty around the World and after Migration

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 
Puberty and reproduction are determined by changes in the secretion of the pituitary gonadotropins, LH and FSH, which are dependent on the frequency and amplitude of pulsatile GnRH neurosecretion from the hypothalamus (1, 9). The timing of puberty can be influenced by signals involving neurotransmitters and neuropeptides that originate in the hypothalamus, in addition to peripheral or gonadal signals. Signals linked to the environment such as nutrition, light, stressors, and endocrine disrupters might impinge on the hypothalamic signaling network directly or through peripheral signals (Fig. 6). In the following sections, we will discuss the possible contribution of hypothalamic, peripheral, and environmental signaling to the differences in timing of puberty around the world and the early activation of the hypothalamic-pituitary-gonadal system in migrating children. It is, however, virtually impossible to isolate the contribution of each signal because many of them are interrelated. Geographical differences might involve altitude, temperature, humidity, and lighting. An underprivileged life setting might involve nutritional problems, high energy expenditure, insufficient public health, individual diseases, large family size, and social and emotional injuries.

View larger version (28K): [in this window] [in a new window]   FIG. 6. Schematic illustration of the relative influences of hypothalamic, peripheral, and environmental signaling on the physiological variability in timing of puberty (A) or the occurrence of a subset with sexual precocity (B) or the shift of the whole study population toward early pubertal timing (C).

It is likely that a cascade of genes may determine variations in timing of pubertal onset. In the rat, manipulation of some homeobox-containing genes (OCT2, TTF-1) involved as regulators of downstream genes of neuropeptides stimulating GnRH secretion such as TGF, can result in alterations of the timing of puberty (141). We have not yet identified, however, the upstream genes that possibly mediate variations related to ethnic and familial patterns of development, as well as the striking sexual dimorphism in onset of puberty. Unraveling those genes will be critical because genetic control can account for most of the physiological variations in pubertal timing whereas peripheral and environmental signals could play relatively minor roles in that respect (Fig. 6A).

The ethnic or racial characteristics belong to the genetically determined factors and could contribute to the sexual precocity of foreign migrating children, in addition to environmental factors. In this respect, studies in migrating people provide an interesting model and put emphasis on environmental factors. In 1942, Ito (142) reported that, in Japanese girls born and reared in California, menarcheal age was more than 1.5 yr earlier than in Japanese girls born in California or Japan and reared in Japan. Although this study put emphasis on environmental factors, the dominant role of genetic factors was emphasized by others who found a similar menarcheal age in Turkish girls living in Germany in comparison with girls living in Turkey (143). Foreign adoption creates a unique situation with children from many different countries and races sharing a similar new setting, although many variables such as importance of former deprivation or insults and age at adoption still account for heterogeneity. In the Belgian experience, sexual precocity could not be related to any clear racial factor because the patients came from different countries all around the world and belonged to different races (17). The percentage of girls seen and treated for precocious puberty was relatively high (1.2%) among those coming from Colombia and India or Sri Lanka compared with other countries. There is a possible bias, however, because adoption from those countries has occurred for many years and at a relatively stable rate throughout the entire study period, whereas that from some other countries (Vietnam, China, Haiti) has started more recently and is still increasing. For instance, many patients with sexual precocity were seen from Haiti in the past few years but not formerly. In addition, differences among countries, such as absence of sexual precocity in girls adopted from Ethiopia or the Philippines, might involve racial and environmental influences, which will be difficult to isolate from each other. In Western Europe, we have relatively few children adopted from Eastern Europe, whereas these countries, particularly Russia and Romania, have provided a great number of children adopted in the United States (119, 123, 144) and among whom early puberty was also common (119, 123). Thus, although racial factors may play some role in the timing of puberty, such a role is relatively minor and unlikely to explain the variations seen in different countries around the world or in migrating children (89).

B. Intrauterine conditions
It has been proposed recently that the intrauterine milieu might influence physiological and pathological events occurring throughout life, although the mechanism of such a programming remains elusive (145). With respect to puberty and reproduction, low birth weight appears to be associated with precocious pubarche (adrenarche) and ovarian hyperandrogenism in the human female (146) and subfertility in the male (147). Evidence of central precocious puberty associated with IUGR has been provided in some patients with Russel-Silver syndrome (148) because, in a review of 148 observations with data on pubertal timing provided for 17 girls and eight boys, eight girls and one boy showed early puberty (149). More recently, precocious puberty was reported in some IUGR patients with maternal uniparental isodisomy of chromosome 14 (150, 151). It is unknown why some particular patients with this syndrome or Russel-Silver syndrome will enter puberty early. Some variations in menarcheal age can be related to low birth weight. In the United Kingdom, the age at menarche was 0.2 yr earlier in girls with birth weight below 2.85 kg compared with those weighing more than 3.75 kg (152). Among Spanish girls with early puberty (B2 between 8 and 9 yr), menarcheal age was 1 yr earlier in girls with a birth weight below 2.7 kg compared with the rest of the cohort (153). In a recent study from Israel, the mean menarcheal age of IUGR girls was found to be advanced by 1.3 yr vs. girls with birth weight appropriate for gestational age, due to increased prevalence of early puberty and reduced prevalence of delayed puberty (154). In a French study, however, IUGR was found to be associated with a pubertal delay averaging 0.8 yr in girls and 2.1 yr in boys, respectively (155). In the general population, some authors found no significant correlation between birth weight and menarcheal age (156), whereas others reported that thin newborns enter puberty earlier (157, 158). A sexual dimorphism in the relationship between birth weight and timing of puberty was observed in a limited group of 35 girls who showed pubertal age positively and significantly correlated with birth weight tertiles, whereas a trend toward a negative correlation was seen in 34 boys (159). The female predisposition to early onset of puberty in IUGR (149, 159) is consistent with the gender dimorphism seen in other etiological conditions. This suggests that factors linked with IUGR are superimposed to a more general mechanism making females prone to develop sexual precocity. Experimental data obtained in rats of both sexes, indicate that IUGR causes delayed puberty in both sexes, whereas early postnatal malnutrition does not affect timing of puberty in the female but causes a delay in the male (160). Thus, alterations in intrauterine conditions are possibly associated with disorders of puberty and reproduction, but their role in physiological variations in timing of puberty remains uncertain.

Could IUGR contribute to sexual precocity in adopted children migrating to Western Europe or the United States? In these children, the likelihood of increased incidence of IUGR is suggested by the Swedish cohort study in which 80% of 37 children with known birth weight were below 2.5 kg (161, 162). Unfortunately, information on birth weight and maternal risk factors for IUGR is lacking in the other studies. In those cases, we can only speculate until collaborative studies are set up between foster and home countries of adopted children. There is no evidence that, in the foreign adopted girls with precocious puberty, a putative IUGR can be linked with premature pubarche as observed in other female populations (146). By contrast, we reported that the development of pubic hair was less advanced in these patients compared with Belgian native girls with idiopathic or organic sexual precocity (163). This finding is consistent with the dissociation between adrenarche and gonadarche (21, 22). The delay in pubic hair development in migrating girls may involve particularly the subset of Indian girls, indicating a possible racial or geographical factor.

C. Nutrition
Among the factors linked with the living standards that account for the downward secular trend in timing of puberty and the differences between underprivileged and privileged settings, nutrition is likely to play a key role. This area appears to be most complex for the following reasons. 1) Nutrition involves both quantitative and qualitative aspects that have been rarely individualized in human studies. 2) Usually, the dietary status is assessed indirectly and incompletely through anthropometry. Weight and the related variables provide some information on storage of metabolic fuels, depending on individual differences in energy balance that may be genetically determined. 3) Reproduction has been more extensively studied than onset of puberty, whereas these two manifestations of pituitary-gonadal function can be differently affected by nutritional signaling. 4) The hypothalamic mechanism controlling food intake/energy balance and onset of puberty/reproduction involves common local and peripheral regulators, which are numerous and act through redundant pathways. 5) The contribution of differences in nutrition to disorders of puberty and reproduction does not mean that nutrition is a determinant of physiological variations in timing of puberty. In this section, we will concentrate on the possible involvement of nutrition in differences in timing of puberty around the world and in migrating children.

A direct relationship between body weight and the age at onset of puberty was suggested by Frisch and Revelle (164, 165) based on comparison between early and late maturers. Frisch et al. (166) concluded that a critical amount of body fat was needed for the onset of puberty. The maintenance of cycling in women has been estimated to require that at least 22% of body composition is fat (167, 168). In the amenorrheic running female monkey, ovulatory cycles are restored by increasing energy availability (169). However, the nutritional determinants of the ovulatory cycle can be different from the control of pubertal timing. The secular decline in menarcheal age occurs together with an opposite trend for regular cycling because, within a 25-yr period, the interval between menarche and regular cycling has increased from 1.9 to 3.0 yr and attains an interval of 5 yr in 21% of women instead of 9% formerly (170). These authors pointed out the possible influence of nutritional changes as well as differences in physical activities among female adolescents. Parallel to the delay in regular cycling, the prevalence of ovulatory disorders seems to increase, pointing to a possible environmental effect as well (171). Nutritional factors also play some role in polycystic ovary syndrome that can, however, predominantly involve genetic factors (172).

The Frisch and Revelle hypothesis has triggered a number of studies that confirmed (41, 156, 173, 174, 175) or did not confirm (28, 176, 177, 178) a significant relationship between menarcheal age and fat mass estimated through BMI or the sum of skinfold thickness or dual energy x-ray absorptiometry. It is debatable whether the Frisch and Revelle hypothesis could be relevant when only the physiological variations in body fatness are considered. As an example, girls with early menarche are more likely to be obese than those with late menarche (156), and, in comparison with nonobese girls, the average menarcheal age of obese girls was 9 months earlier in Japan (67) and 0.9 yr earlier in Thailand (179). However, the mechanisms involved in these pathological conditions may be different from those in normal subjects. Another difficult issue is the meaning of a significant correlation between fatness and menarcheal age. This may indicate a direct relation between fatness and menarche that can be either causal or consequential. Alternatively, the link between the two parameters can only be indirect because they share similar genetic determinants. In this respect, the recent study by Wang (180) is interesting because early sexual maturation is associated with an increased prevalence of fatness in girls and leanness in boys. Such a sexual dimorphism could involve genetic and/or endocrine factors. Several authors reported that early menarche was associated with an increased risk of obesity in adulthood (181, 182). Conversely, several studies suggested that childhood might be a critical period for weight to influence the timing of puberty because menarcheal age was inversely related to weight at 7 yr (152). Qing and Karlberg (183) reported that a gain in 1 U of BMI between 2 and 8 yr was associated with an advancement of age at the pubertal growth spurt reaching 0.6 yr in boys and 0.7 yr in girls. Davison et al. (184) reported that early onset of breast development by 9 yr could be weakly but significantly predicted by a higher percentage body fat at 5 and 7 yr. In this study, up to 14 and 35% of girls reached B2 stage at 7 and 9 yr, respectively, which was assessed, however, by visual inspection only. Kaprio et al. (3) suggested that the association between relative body weight and menarcheal age was primarily due to correlated genetic effects, whereas the two parameters were influenced by separate environmental correlates independent of each other. Karlberg (158) came to a similar conclusion about peak height velocity and menarche, which can occur simultaneously or at a time interval of 2 yr. They also emphasized the halt in secular trend in menarcheal age while height (and weight) are still increasing. It is tempting to conclude that the link between nutritional status and physiological variations in timing of puberty can be significant but is not particularly strong, suggesting that the relationship is indirect or partial and superseded by other factors.

Is there any possible link between the anthropometric data and the ethnic variations in pubertal timing? In some studies, only a minor advancement of 0.1–0.3 yr in menarcheal age was observed in African-American girls as compared with white American girls (35, 41). That advancement was found to be 0.4 yr in the NHANES III cohort (39) and reached 0.7 yr in the PROS study (6), which raised the question of whether racial differences in nutrition and weight for height play any role. Recently, Anderson et al. (40) found that the racial differences in menarcheal age were independent of differences in BMI. In another recent study, African-American girls were found to be fatter and sexually more mature than white American girls, a difference that was associated with increased levels of free bioavailable IGF-I (185). These data, however, are not comparable to the PROS study (6) because pubic hair, which was used as the marker of sexual maturation, may provide information on adrenarche but not gonadarche. There are additional ethnic differences, including higher insulin response to a glucose challenge among black vs. white subjects, lower resting energy expenditure, and perhaps less physical activity (186), without evidence, so far, of contribution to the racial differences in pubertal timing. Kaplowitz et al. (187) used the growth data from the PROS study (6) to calculate the SD scores (SDS) or Z scores of BMI. They found these scores to increase at the time of onset of breast development and concluded that the gain in BMI was predictive of onset of puberty and consistent with the racial difference in pubertal timing. Again, this conclusion raises the above debate about the causal or consequential nature of the observed correlation. In addition, there is a possible bias in these study conditions because BMI reference data from average maturers were used to calculate Z scores in early maturers. Likewise, in the recent report by Wang (180), the definition of overweight in early maturers using the BMI percentiles obtained in average maturers can involve a similar bias. If an increase in BMI occurs early as a possible consequence of early pubertal development, the reference data from average maturers provide inappropriately low values to calculate Z scores of BMI in early maturers. This may result in overestimation of BMI increase and can mistakenly lead to the conclusion that such an increase has a causal influence on pubertal onset.

Studies assessing directly the influence of dietary intake on the age at menarche have not shown any clear correlation between diets and timing of puberty. A weak but statistically significant correlation was found between early menarche and energy intake and expenditure (173). In contrast, high vs. low energy intake was associated with later menarcheal age in heavy Hispanic girls in California, which might have been caused by underreporting of the dietary intake in some groups (188). The protein source of food in early life could also influence the timing of puberty because a high animal vs. vegetable protein ratio at the ages of 3–5 yr is associated with early menarche, after controlling for body size (189). Phytoestrogens in the diet might have a role in the regulation of puberty both directly and indirectly (190). They interact with estrogen receptors and may have either agonistic or antagonistic effects, depending on the endogenous hormonal balance (191). In prepubertal boys who have very low endogenous estrogen levels, phytoestrogens might have some agonistic effects, whereas antagonistic effects would be expected when endogenous estrogen levels are higher. It was shown in the rat that the phytoestrogen coumestrol caused both reduced frequency of the electrophysiological hypothalamic discharges associated with pulsatile LH secretion as well as direct pituitary inhibition (192). In addition to their receptor effects, phytoestrogens affect the metabolism of hormones. They have been shown to inhibit aromatase and 17ß-hydroxysteroid dehydrogenase type 1 and type 5 enzymes (193, 194, 195, 196). Thus, the sum effect of phytoestrogens appears clearly antiestrogenic, which is also in accordance with animal experiments (197). A phytoestrogen-rich diet might therefore delay puberty as demonstrated by Berkey et al. (189). Such a conclusion may be relevant to the nutritional changes that can be involved in early puberty after migration because vegetable products such as soybean or cassava are major food components in developing countries but not in Western European societies (198).

Underfed children have delayed puberty (199), and, in many children adopted from foreign countries, malnutrition at arrival has been reported. The mean SDS of weight for height at arrival was –0.6 in the Swedish study (161, 162), and the weight deficit was –10.5% in the Italian study (14). In such conditions, a catch up in height and weight is commonly seen after arrival and precedes early sexual maturation. This has led to the hypothesis that hormonal events linked with catch-up growth may prime hypothalamic maturation and lead to puberty. This hypothalamic priming was thought to possibly occur in a critical age window because precocious menarche (<10 yr) was more common in Indian girls who arrived in Sweden between 3 and 6 yr than in those who arrived before 2 yr of age (11). The concept of a critical prepubertal period for nutritional priming of maturation is in agreement with observations in healthy boys and girls (152, 183, 184). Proos (200) reported that, in foreign adopted children, earlier menarche was correlated with later age at immigration and faster catch up in height and weight after immigration. He found, however, in a multiple linear regression analysis, that menarcheal age was associated with height at immigration but not with age at immigration. In a study of 65 Romanian adoptees in the United States, Johnson et al. (144) found that only 15% of them were mentally and physically healthy at arrival. These authors observed that growth failure was directly correlated with duration of institutionalization, every 3 months of life in an orphanage resulting in a loss of 1 month in height age. They also reported that weight was usually less compromised than height, suggesting that nutritional deprivation might play a less prominent role than other factors such as genetics, prematurity, IUGR, medical illnesses, and stress. A catch-up growth was also noticed after adoption, with a greater extent of recovery in children adopted before 18 months than in those adopted at later ages (144).

Whereas the impact of nutritional deprivation and restoration after migration may be crucial in some foreign children who develop sexual precocity, others have normal weight and height at arrival. In the French study, the mean SDS of weight for height of foreign adopted children was +1.2 at immigration (16). In the Belgian series, the mean SDS of BMI was –0.2 at arrival, indicating normal weight for height on average (17). The interpretation of height and weight data in adopted children, however, should be cautious because the Western European or North American references may not be applicable. In a study of Indian adolescent boys who showed peak height velocity at an average age of 13, which is similar to American boys, the prevalence of height and BMI below the fifth centile using the NCHS references was 11 and 50%, respectively (201). In addition, the proportion of obese and wasted children was not necessarily reciprocal, and variability among countries was considerable (202). Quite interestingly, the observation of precocious puberty in nonadopted foreign children migrating to Belgium together with their original families and without evidence of former nutritional or affective deprivation (17) provides further support to the role of factors other than nutrition in relation to the changing environment. To mimic catch-up growth after immigration in formerly deprived foreign children, early underfeeding and refeeding was used in the rat, and the effects were studied on hypothalamic glutamate neurotransmission, which is a major trigger of pulsatile GnRH secretion (1, 203). An acceleration of maturation of the glutamate receptor-dependent secretion of GnRH occurred after refeeding and was maximal at a particular postnatal age period (12). These data suggest the involvement of hypothalamic glutamate receptors in the pathophysiology of that form of sexual precocity.

Whether fat-derived signals, such as leptin, or body-size linked signals, such as IGF-I, or other factors related to energy availability, such as glucose, are essential for timing of puberty and regulation of reproduction remains a matter of debate (204, 205). Peripheral leptin signaling is likely to be permissive only in physiological conditions (Fig. 5), as suggested by the controversial studies throughout normal development in human and subhuman primates (205, 206). In some nonphysiological conditions, leptin appears to be a prerequisite to normal hypothalamic-pituitary-gonadal function (205, 207), confirming rodent studies (208, 209, 210). In girls with sexual precocity, controversial data have been obtained because modestly but consistently increased serum levels of leptin were observed by Palmert et al. (211), whereas no difference in BMI-adjusted levels was found by Heger et al. (212). Another recent candidate messenger between nutritional status/energy balance and the hypothalamus is ghrelin (213), which we found to be capable of stimulation of pulsatile GnRH secretion from prepubertal rat hypothalamic explants (214). In conditions with impaired and restored nutrition, other endocrine changes, such as increased secretion of IGF-I, may occur during catch-up growth and act as a mediator between the environment and the hypothalamus. Although a role of IGF-I has been advocated for many years, its contribution remains equivocal (215, 216). Acute effects of glucose on pulsatile LH secretion have been shown in the lamb (217), but not in the rhesus monkey (218). As reviewed by Cameron (219), different metabolic signals, including glucose, insulin, and leptin, are capable of modulating reproductive axis activity under specific circumstances, but their physiological role remains unknown. A potentially important contribution of sex steroids in the hypothalamic effects of environmental signals is suggested by the reduced expression of hypothalamic estrogen receptors after food restriction (220, 221). Thyroid hormones can be a mediator of environmental effects as well (222). This indicates the complexity of the potential neuroendocrine interactions between nutritional conditions and puberty, including the role of estrogen receptors such as already discussed in Section IV.A. In addition, there are possible peripheral effects of some forms of undernutrition (kwashiorkor, anorexia nervosa) resulting in increased serum concentrations of SHBG which are reduced by refeeding and may affect the bioavailability of sex steroids (223, 224).

D. Other stresses
Different stresses, such as acute or chronic illnesses and adverse physical or psychological conditions, are known to depress the hypothalamic-pituitary-gonadal system (225, 226). Intensive physical training and sport competition, such as in elite gymnasts, can result in combined physical, psychological, and nutritional stresses that are associated with delayed puberty or late menarche (227, 228). In war conditions, which involve nutritional deprivation and psychological or emotional insult such as occurred in Bosnia and Croatia, a delay in menarcheal age or a reversal of the secular trend was observed (229, 230). In these chronic conditions, it is difficult to isolate the participation of each stress factor. Some acute stress situations may not result in observable effects on menarcheal age as shown in tribal girls undergoing female circumcision at adolescence (231). In another acute situation, such as fasting-induced suppression of LH secretion, metabolic signals were shown to play a more important role than psychological stress (232). The relative difference in impact of the components of a stressful situation is further suggested by the heterogeneity of the neuroendocrine response to various acute stressors, indicating that they are signaling through specific pathways (233). Among the neuronal circuits involved, signaling through CRH and IL-1 may be particularly important (234). Thus, it is possible that, in foreign migrating children, withdrawal from a stressful environment contributes to potentiation of maturation, although some stress may result from the adoption and migration processes as well. The latter hypothesis might be consistent with the observation of early pubertal development in conditions of stressful rearing and insecure attachment to parents (235, 236).

E. Light-darkness cycle and climatic conditions
Environmental signals related to climate and light deserve some attention in the context of variations in pubertal timing around the world, as well as migrating children with sexual precocity. Temperature and light-darkness rhythms that are influenced by geography and seasons might modulate the reproductive axis. As discussed above (Fig. 2), a north-south gradient in menarcheal age around the world has suggested the possible influence of climatic conditions although most observations indicate that climate in itself has little or no effect on menarche (89). In Caucasian Jewish high school girls, menarche is earlier in the hot city of Elat than in the temperate city of Safad (237). In the 1950s, however, Zacharias and Wurtman (89) observed a similar menarcheal age in Nigerian (238) and Alaskan Eskimo girls (239).

Indirect evidence of a role of exposure to light in human puberty comes from the fact that blind girls have earlier menarche than normal (240, 241) although these reports were not confirmed subsequently. Several studies have suggested that menarche starts relatively more frequently in winter than in summer in normal girls (242, 243, 244), suggesting an inhibitory effect of photostimulation. However, in the Arctic area, the dark winter months may be associated with reduced pituitary-gonadal function and low conception rates (245). Thus, the influences of light and temperature on the human reproductive axis are uncertain and rather minor as compared with the seasonally breeding animals. The effects of light-darkness rhythms can be mediated through the pineal gland hormone, melatonin, which circulates in high concentrations at night. Melatonin is inhibitory to the neonatal rat pituitary gland (246), whereas its neonatal administration accounts for sexual precocity (247, 248). In man, because a fall in peripheral melatonin concentrations occurs during the peripubertal period (249, 250, 251), a role for melatonin in the onset of puberty has been proposed, which is further supported by observations in sexual precocity and hypogonadotrophic hypogonadism (252, 253). The most obvious decrease in melatonin secretion, however, occurs after onset of puberty, between Tanner stages II and III (251). This might suggest that melatonin secretion decreases as a consequence of increase in sex steroid levels at puberty, a concept further supported by studies in isolated gonadotropin deficiency and delayed puberty (254). The role of melatonin in human puberty warrants further longitudinal and mechanistic studies correlating melatonin secretion with other hormonal parameters. An influence of seasonal factors on sexual precocity in migrating children cannot be excluded at this point, although the average period of 4 yr between migration and early onset of puberty (17) is inconsistent with the time sequence of changes in melatonin secretion and puberty in normal children.

F. Exposure to endocrine-disrupting chemicals (EDCs)
EDCs are widespread environmental substances that have been introduced by man and that may influence the endocrine system in a harmful manner (255, 256). EDCs account for several disturbances in wildlife (257) and may also play a role (256, 258) in human disorders of sex differentiation and of reproductive organs and functions. Also, the possible role of EDCs in development of hormone-dependent cancers such as breast cancer is a matter of concern, although the data are controversial (259). Krstevska-Konstantinova and co-workers (17) have hypothesized that moving to Belgium could result in a change in exposure to EDCs when a child moves from the home country to the foster country, thus causing sexual precocity to occur. The screening for eight organochlorine pesticides in serum of foreign migrating patients with precocious puberty in comparison with Belgian native patients has revealed the presence of p,p'-DDE [1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene] in migrating children (17). p,p'-DDE is a persistent derivative of the insecticide DDT [1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane] with a half-life of several decades. DDT has been banned in the United States and Western European countries since the late 1960s (104, 260) but is still used extensively in developing countries. DDT and some isomers behave as estrogen agonists and/or androgen antagonists (261, 262). In 26 foreign patients (15 adopted and 11 nonadopted) with precocious puberty, the mean serum concentration of p,p'-DDE was 10 times higher than the limit of detection, whereas the levels were below this limit in 13 of 15 Belgian native patients (17). Three of the foreign patients were born in Belgium and showed elevated serum levels of p,p'-DDE, suggesting a transplacental or lactational route of exposure. The latter hypothesis is consistent with the lipophilic nature and bioaccumulating capacity of DDT and other widespread endocrine-disrupting compounds such as polychlorinated and polybrominated biphenyls. Also, the possible relationship between sexual precocity and fetal or perinatal exposure to EDCs is raising the issue of the period of exposure during development, a possibly critical parameter (263, 264). Recently, a 32% fall in probability of pregnancy in 28- to 31-yr-old daughters was found to be associated with 10 µg/liter of p,p'-DDT in mother’s serum drawn around the time of delivery (265). Although the mechanism underlying such an association is unclear, it indicates the importance of very long-term studies, as in the case of diethylstilbestrol (266). In the Belgian study (17, 267), it was likely that the p,p'-DDE levels resulted from contamination in the country of origin because they were correlated positively with age at immigration and negatively with time since immigration (Fig. 7). However, in addition to DDT contamination in the country of origin, exposure to other EDCs in both the country of origin and the foster country is quite likely and should be considered in the mechanistic approach. This is a most difficult issue because the number of potential EDCs is increasing dramatically in the environment, and isolation of the responsible agent or mixture of agents is usually not possible. As an example, it was reported very recently that a blood lead concentration of 3 µg/dl was associated with delayed breast and pubic hair development in black American girls but not in white girls (268 ). Another recent study came to slightly different conclusions because increased lead levels were associated with delayed pubic hair and menarche but not with breast development in a mixed cohort of American girls (269). In migrating children, the link between DDT and sexual precocity is only correlative at this point, and DDT contamination is an expected finding in any child migrating from a developing country. Thus, the demonstration of DDT involvement in the pathogenesis of sexual precocity warrants further comparison with foreign migrating children who had normal or even delayed puberty. In addition to the estrogenic effects of EDCs, they may also cause antiandrogenic effects that could explain the delay in pubic hair development (see above), although ethnicity may play a role as well.

View larger version (18K): [in this window] [in a new window]   FIG. 7. Serum levels of p,p'-DDE, a derivative of the organochlorine pesticide DDT in different patients with sexual precocity. The Belgian native patients have central precocious puberty of organic or idiopathic origin. The foreign migrating patients with sexual precocity are adopted or nonadopted. The data of foreign patients are represented in relation to age at immigration and time since immigration.

	V. Conclusion and Future Research Directions

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 
The variations in age at onset of puberty involve different components including the average timing, the pattern of age distribution, and the variability, which is the difference between average and upper/lower age limits. The differences in average timing of puberty among countries around the world have become relatively small because they do not exceed 1 yr in well-off conditions, and the secular trends have been less marked than before the 1960s except in conditions of undernutrition. In contrast, an important individual variability in physiological pubertal timing that attains 4–5 yr is consistently seen despite optimal or improved living standards in most countries. In addition, new forms of sexual precocity are seen, such as in children migrating from developing countries. As summarized schematically in Fig. 6A, this individual variability, which involves familial, ethnic, and gender patterns, is likely to depend on the genetic control of the expression of signals or signal receptors in the hypothalamus. This process is only slightly influenced by peripheral and environmental signals, which play an essentially permissive role in those conditions. In specific situations, however, these peripheral and environmental signals may play a crucial role in the occurrence of either abnormal precocious (or delayed) puberty in a subset of a population (Fig. 6B) or increased incidence of precocity (or delay) because of a shift in timing of a whole population (Fig. 6C). The latter situation is consistent with the recently demonstrated advancement in onset of breast development in the United States, where revised limits for sexual precocity were proposed. No similar changes were evidenced in Europe, where the age criteria for precocious puberty have remained unchanged. Whether such discrepant observations involve differences in nutrition or living standards and/or the recently postulated effects of endocrine disruptors remains to be elucidated. A challenging observation that put emphasis on the environmental factors is the overall early age at onset of puberty and the increased incidence of sexual precocity in foreign children who migrate from developing countries to Western Europe and, probably, to the United States as well. However, there is no simple and single explanation to this phenomenon. Further studies should evaluate the effects of migration by comparing the timing and dynamics of pubertal development in both the developing and developed countries. A combination of epidemiological, toxicological, and endocrinological studies is warranted to better delineate the possible role of EDCs because precocious puberty in migrating children may represent an additional example of the undesirable effects of emerging environmental chemicals. In a broader sense, this review has integrated timing of puberty and its disorders within a spectrum of physiological processes or diseases throughout life (Fig. 8). Several more or less strong associations have been observed between intrauterine growth, sex differentiation, pubertal timing, fertility, fat mass, sensitivity to insulin, and cancer risk. Nonfortuitous associations of disorders involving these processes have been proposed as the testicular dysgenesis syndrome in the male with hypospadias, cryptorchidism, reduced sperm count, and testicular cancer (258) and a polyendocrine-metabolic syndrome in the female with IUGR, precocious pubarche, ovarian hyperandrogenism, ovulatory dysfunction, hyperinsulinism, and dyslipemia (146). Such associations may be determined by both genetic factors and environmental hits that may be common to some of those manifestations. Along this line, the timing of puberty may be one early sensor of the effects of genetics and environment, these two components being often combined. This is a continuing challenge for both researchers and clinicians.

View larger version (32K): [in this window] [in a new window]   FIG. 8. Integration of timing of puberty within a spectrum of processes that are influenced by both genetic and environmental factors. This concept may explain the nonfortuitous association of disorders in the testicular dysgenesis syndrome described in the male (258 ) and the polyendocrine-metabolic syndrome in the female (146 ).

	Acknowledgments

 
We are grateful to Dr. O. H. Pescovitz for helpful comments.

	Footnotes

 
A.-S.P. is a research fellow of the Belgian "Fonds National de la Recherche Scientifique" (FNRS). G.T. was supported by The Health Insurance Foundation and The Research Foundation of Queen Louises Childrens Hospital. This work was supported by the Fonds de la Recherche Scientifique Médicale (Grant 3.4515.01), the Belgian Study Group for Pediatric Endocrinology, and The European Commission (contract no. QLRT-2001-00269).

Abbreviations: BMI, Body mass index; CV, coefficient of variation; DDE, 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene; DDT, 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane; EDCs, endocrine-disrupting chemicals; IUGR, intrauterine growth retardation; NHANES, National Health and Nutrition Examination Survey; NHES, National Health Examination Survey; PROS, Pediatric Research in Office Settings; SDS, SD score.

	References

Top Abstract I. Introduction II. Normal Puberty and... III. Precocious Puberty IV. Possible Mechanisms of... V. Conclusion and Future... References

 

1. Terasawa E, Fernandez DL 2001 Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 22:111–151[Abstract/Free Full Text]
2. Tanner JM 1962 Growth at adolescence. 2nd ed. Oxford, UK: Blackwell
3. Kaprio J, Rimpela A, Winter T, Viken RJ, Rimpela M, Rose RJ 1995 Common genetic influences on BMI and age at menarche. Hum Biol 67:739–753[Medline]
4. Van Wieringen JC 1978 Secular growth changes. In: Falkner F, Tanner JM, eds. Human growth. New York: Plenum Press; 445–473
5. Eveleth PB 1978 Population differences in growth: environmental and genetic factors. In Falkner F, Tanner JM, eds. Human growth. New York: Plenum Press; 373–394
6. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM 1997 Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99:505–512[Abstract/Free Full Text]
7. NHANES III 1997 NHANES III Reference manuals and reports (CD-ROM). Analytic and reporting guidelines: the Third National Health and Nutrition Examination Survey (1988–94). Hyattsville, MD: National Center for Health Statistics, Centers for Disease Control and Prevention
8. Lee PA, Guo SS, Kulin HE 2001 Age of puberty: data from the United States of America. APMIS 109:81–88[CrossRef][Medline]
9. Grumbach MM, Styne DM 1998 Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams’ textbook of endocrinology. 9th ed. Philadelphia: W.B. Saunders Co; 1509–1625
10. Bridges NA, Christopher JA, Hindmarsh PC, Brook CG 1994 Sexual precocity: sex incidence and aetiology. Arch Dis Child 70:116–118[Abstract/Free Full Text]
11. Proos LA, Hofvander Y, Tuvemo T 1991 Menarcheal age and growth pattern of Indian girls adopted in Sweden. I. Menarcheal age. Acta Paediatr Scand 80:852–858[Medline]
12. Bourguignon JP, Gerard A, Alvarez Gonzalez ML, Fawe L, Franchimont P 1992 Effects of changes in nutritional conditions on timing of puberty: clinical evidence from adopted children and experimental studies in the male rat. Horm Res 38(Suppl 1):97–105
13. Oostdijk W, Yap YN, Slijper FME, Wit JM, Drop SLS 1996 Puberteit en eindlengte bij uit het buitenland geadopteerde kinderen. Tijdschr Kindergeneeskd 64:39–43
14. Virdis R, Street ME, Zampolli M, Radetti G, Pezzini B, Benelli M, Ghizzoni L, Volta C 1998 Precocious puberty in girls adopted from developing countries. Arch Dis Child 78:152–154[Abstract/Free Full Text]
15. de Monleon JV, Geneste B, Huet F 1999 Puberté précoce chez les enfants adoptés, un risque à ne pas oublier. Arch Pediatr 6:589–590[Medline]
16. Baron S, Battin J, David A, Limal JM 2000 Puberté précoce chez des enfants adoptés de pays étrangers. Arch Pediatr 7:809–816[CrossRef][Medline]
17. Krstevska-Konstantinova M, Charlier C, Craen M, Du Caju M, Heinrichs C, de Beaufort C, Plomteux G, Bourguignon JP 2001 Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Hum Reprod 16:1020–1026[Abstract/Free Full Text]
18. Teilmann G, Main K, Skakkebaek N, Juul A 2002 High frequency of central precocious puberty in adopted and immigrant children in Denmark. Horm Res 58(Suppl 2):135 (Abstract)
19. Marshall WA, Tanner JM 1970 Variations in the pattern of pubertal changes in boys. Arch Dis Child 46:13–23
20. Tanner JM, Whitehouse RH 1976 Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51:170–179[Abstract/Free Full Text]
21. Sklar CA, Kaplan SL, Grumbach MM 1980 Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence. J Clin Endocrinol Metab 51:548–556[Abstract/Free Full Text]
22. Palmert MR, Hayden DL, Mansfield MJ, Crigler Jr JF, Crowley Jr WF, Chandler DW, Boepple PA 2001 The longitudinal study of adrenal maturation during gonadal suppression: evidence that adrenarche is a gradual process. J Clin Endocrinol Metab 86:4536–4542[Abstract/Free Full Text]
23. Hergenroeder AC, Hill RB, Wong WW, Sangi-Haghpeykar H, Taylor W 1999 Validity of self-assessment of pubertal maturation in African-American and European-American adolescents. J Adolesc Health 24:201–205[CrossRef][Medline]
24. Berg-Kelly K, Erdes L 1997 Self-assessment of sexual maturity by mid-adolescents based on a global question. Acta Paediatr 86:10–17[Medline]
25. Marti-Henneberg C, Louw GJ 1995 Average menarcheal age of higher socioeconomic status urban Cape coloured girls assessed by means of status quo and recall methods. Am J Phys Anthropol 96:1–5[CrossRef][Medline]
26. Koo MM, Rohan TE 1997 Accuracy of short-term recall of age at menarche. Ann Hum Biol 24:61–64[CrossRef][Medline]
27. Artaria MD, Marti-Henneberg C 2000 Why did they lie? Socio-economic bias in reporting menarcheal age. Ann Hum Biol 27:561–569[CrossRef][Medline]
28. de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB 1992 Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab 75:442–446[Abstract]
29. Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage: therapeutic implications. Endocr Rev 9:467–488[Abstract/Free Full Text]
30. Marti-Henneberg C, Vizmanos B 1997 The duration of puberty in girls is related to the timing of its onset. J Pediatr 131:618–621[CrossRef][Medline]
31. Tanner JM, Davies PSW 1985 Clinical longitudinal standards for height and height velocity for North American children. J Pediatr 107:317–329[CrossRef][Medline]
32. Carrillo JC, Ireton MJ, Caro LE, Hauspie R, Morales JC, Pagezy H 2001 Growth traits and sexual maturation in a sample of schoolchildren from El Yopal, Casanare, Colombia. Acta Med Auxol 33:105–111
33. Ducros A, Pasquet P 1978 Evolution de l’âge d’apparition des premières règles (ménarche) en France. Biometrie Humaine 13:35–43
34. Warren MP 1983 Effects of undernutrition on reproductive function in the human. Endocr Rev 4:363–377[Abstract/Free Full Text]
35. Mac Mahon B 1973 Age at menarche, United States. DHEW Pub. no. (HRA) 74-1615 Natl Health Surv 133
36. Rosenfield RL, Bachrach LK, Chernausek SD, Gertner JM, Gottschalk M, Hardin DS, Pescovitz OH, Saenger P 2000 Current age of onset of puberty. Pediatrics 106:622–623[Free Full Text]
37. Lee PA, Kulin HE, Shumei SG 2001 Letter to the editor: age of puberty among girls and the diagnosis of precocious puberty. Pediatrics 107:1493–1494[Free Full Text]
38. Sun SS, Schubert CM, Chumlea WC, Roche AF, Kulin HE, Lee PA, Himes JH, Ryan AS 2002 National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 110:911–919[Abstract/Free Full Text]
39. Chumlea WC, Schubert CM, Roche AF, Kulin HE, Lee PA, Himes JH, Sun SS 2003 Age at menarche and racial comparisons in US girls. Pediatrics 111:110–113[Abstract/Free Full Text]
40. Anderson SE, Dallal GE, Must A 2003 Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart. Pediatrics 111:844–850[Abstract/Free Full Text]
41. Wattigney WA, Srinivasan SR, Chen W, Greenlund KJ, Berenson GS 1999 Secular trend of earlier onset of menarche with increasing obesity in black and white girls: the Bogalusa Heart study. Ethn Dis 9:181–189[Medline]
42. Freedman DS, Srinivasan SR, Valdez RA, Williamson DF, Berenson GS 1997 Secular increases in relative weight and adiposity among children over two decades: the Bogalusa heart study. Pediatrics 99:420–426[Abstract/Free Full Text]
43. Troiano RP, Flegal KM, Kuczmarski RJ, Campbell SM, Johnson CL 1995 Overweight prevalence and trends for children and adolescents. Arch Pediatr Adolesc Med 149:1085–1091[Abstract/Free Full Text]
44. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL 1994 Increasing prevalence of overweight among US adults. JAMA 272:205–211[Abstract/Free Full Text]
45. Freedman DS, Kettel Khan L, Serdula MK, Dietz WH, Srinivasan SR, Berenson GS 2002 The relation of age at menarche to race, time period, and anthropometric dimensions: the Bogalusa Heart Study. Pediatrics 110:43–49
46. Biro FM, McMahon RP, Striegel-Moore R, Crawford PB, Obarzanek E, Morrison JA, Barton BA, Falkner F 2001 Impact of timing of pubertal maturation on growth in black and white female adolescents: The National Heart, Lung, and Blood Institute Growth and Health Study. J Pediatr 138:636–643[CrossRef][Medline]
47. Harlan WR, Harlan EA, Grillo GP 1980 Secondary sex characteristics of girls 12 to 16 years of age: the US Health Examination Survey. J Pediatr 96:1074–1078[CrossRef][Medline]
48. De Muinck Keizer-Schrama SMPF, Mul D 2001 Trends in pubertal development in Europe. Hum Reprod Update 7:287–291[Abstract/Free Full Text]
49. Rimpelä AH, Rimpelä MK 1993 Towards an equal distribution of health? Socioeconomic and regional differences of the secular trend of the age at menarche in Finland from 1979 to 1989. Acta Paediatr 82:87–90[Medline]
50. Lindgren GW, Degerfors IL, Fredriksson A, Loukili A, Mannerfeldt R, Nordin M, Palm K, Petterson M, Sundstrand G, Sylvan E 1991 Menarche 1990 in Stockholm schoolgirls. Acta Paediatr Scand 80:953–955[Medline]
51. Lindgren G 1996 Pubertal stages 1980 of Stockholm schoolchildren. Acta Paediatr 85:1365–1367[Medline]
52. Helm P, Grolund L 1998 A halt in the secular trend towards earlier menarche in Denmark. Acta Obstet Gynecol Scand 77:198–200[CrossRef][Medline]
53. Buckler J 1990 A longitudinal study of adolescent growth. London: Springer-Verlag
54. Rees M 1993 Menarche when and why? Lancet 342:1375–1376[CrossRef][Medline]
55. Engelhardt L, Willers B, Pelz L 1995 Sexual maturation in East German girls. Acta Paediatr 84:1362–1365[Medline]
56. Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ, Brugman E, Roede MJ, Verloove-Vanhorick SP, Wit JM 2000 Continuing positive secular growth change in the Netherlands 1955–1997. Pediatr Res 47:316–323[Medline]
57. Mul D, Fredriks M, van Buuren S, Oosdijk W, Verloove- Vanhorick SP, Wit JM 2001 Pubertal development in The Netherlands 1965–1997. Pediatr Res 50:479–486[Medline]
58. Vercauteren M, Susanne C 1985 The secular trend of height and menarche in Belgium: are there any signs of a future stop? Eur J Pediatr 144:306–309[CrossRef][Medline]
59. Largo RH, Prader A 1983 Pubertal development in Swiss girls. Helv Paediatr Acta 38:229–243[Medline]
60. de La Rochebrochard E 1999 Les âges à la puberté des filles et des garçons en France. Population 54:933–962
61. Borneman M, Vienna A, Tommaseo M, Capucci E 1995 Menarcheal age and environmental factors in a sample from the province of Rome. Acta Med Auxol 27:97–104
62. de la Puente ML, Canela J, Alvarez J, Salleras L, Vicens-Calvet E 1997 Cross-sectional growth study of the child and adolescent population of Catalonia (Spain). Ann Hum Biol 24:435–452[CrossRef][Medline]
63. Rueda C, Labena C, Boldova C, Leon E, Labarta J, Mayayo E, Ferrandez Longas A 2002 Spanish longitudinal study of growth and development: pubertal development standards. Horm Res 58(Suppl 2):36 (Abst)
64. Papadimitriou A, Gousia E, Pitaouli E, Tapaki G, Philippidis P 1999 Age at menarche in Greek girls. Ann Hum Biol 26:175–177[CrossRef][Medline]
65. Eveleth PB, Tanner JM 1990 Worldwide variation in human growth, 2nd ed. Cambridge, UK: Cambridge University Press
66. Huen KF, Leung SS, Lau JT, Cheung AY, Leung NK, Chiu MC 1997 Secular trend in the sexual maturation of Southern Chinese girls. Acta Paediatr 86:1121–1124[Medline]
67. Murata M, Hibi I 1992 Nutrition and the secular trend of growth. Horm Res 38(Suppl 1):89–96
68. Rao S, Joshi S, Kanade A 1998 Height velocity, body fat and menarcheal age of Indian girls. Indian Pediatr 35:619–628[Medline]
69. Chompootaweep S, Tankeyoon M, Poomsuwan P, Yamarat K, Dusitsin N 1997 Age at menarche in Thai girls. Ann Hum Biol 24:427–433[CrossRef][Medline]
70. Ruiz A, Blanco R, Santander J, Miranda E 2000 Relationship between sex differences in onset of schizophrenia and puberty. J Psychiatr Res 34:349–353[CrossRef][Medline]
71. Macias-Tomei C, Lopez-Blanco M, Espinoza I, Vasquez-Ramirez M 2000 Pubertal development in Caracas upper-middle-class boys and girls in a longitudinal context. Am J Hum Biol 12:88–96[CrossRef][Medline]
72. Pasquet P, Biyong AM, Rikong-Adie H, Befidi-Mengue R, Garba MT, Froment A 1999 Age at menarche and urbanization in Cameroon: current status and secular trends. Ann Hum Biol 26:89–97[CrossRef][Medline]
73. Cameron N, Wright CA 1990 The start of breast development and age at menarche in South African black females. S Afr Med J 78:536–539[Medline]
74. Largo RH, Prader A 1983 Pubertal development in Swiss boys. Helv Paediat Acta 38:211–228
75. Herman-Giddens ME, Wang L, Koch G 2001 Secondary sexual characteristics in boys. Estimates from the National Health and Examination Survey III, 1988–1994. Arch Pediatr Adolesc Med 155:1022–1028[Abstract/Free Full Text]
76. Reiter EO, Lee PA 2001 Editorial: Have the onset and tempo of puberty changed? Arch Pediatr Adolesc Med 155:988–989[Free Full Text]
77. Harlan WR, Grillo GP, Cornoni-Huntley J, Leaverton PE 1979 Secondary sex characteristics of boys 12 to 17 years of age: the US Health Examination Survey. J Pediatr 95:293–297[CrossRef][Medline]
78. Roche AF, Wellens R, Attie KM, Siervogel RM 1995 The timing of sexual maturation in a group of US white youths. J Pediatr Endocrinol Metab 8:11–18[Medline]
79. Biro FM, Lucky AW, Huster GA, Morrison JA 1995 Pubertal staging in boys. J Pediatr 127:100–102[CrossRef][Medline]
80. Wong GW, Leung SS, Law WY, Yeung VT, Lau JT, Yeung WK 1996 Secular trend in the sexual maturation of southern Chinese boys. Acta Paediatr 85:620–621[Medline]
81. Willers B, Engelhardt L, Pelz L 1996 Sexual maturation in East German boys. Acta Paediatr 85:785–788[Medline]
82. Farid-Coupal N, Contreras ML, Castellano HM 1981 The age at menarche in Carabobo, Venezuela with a note on the secular trend. Ann Hum Biol 8:283–288[CrossRef][Medline]
83. Singh SP, Malhotra P 1988 Secular shift in menarcheal age of Patiala (India) schoolgirls between 1974 and 1986. Ann Hum Biol 15:77–80[CrossRef][Medline]
84. Ekele BA, Udoeyop EU, Otubu JA 1996 Age at menarche amongst school girls in a high altitude Nigerian town. West Afr J Med 15:170–172[Medline]
85. Khan AD, Schroeder DG, Martorell R, Rivera JA 1995 Age at menarche and nutritional supplementation. J Nutr 125(Suppl 4):1090–1096
86. Graham MJ, Larsen U, Xu X 1999 Secular trend in age at menarche in China: a case study of two rural counties in Anhui Province. J Biosoc Sci 31:257–267[CrossRef][Medline]
87. Simondon KB, Simon I, Simondon F 1997 Nutritional status and age at menarche of Senegalese adolescents. Ann Hum Biol 24:521–532[CrossRef][Medline]
88. Thomas F, Renaud F, Benefice E, de Meeus T, Guegan JF 2001 International variability of ages at menarche and menopause: patterns and main determinants. Hum Biol 73:271–290[Medline]
89. Zacharias L, Wurtman RJ 1969 Age at menarche. Genetic and environmental influences. N Engl J Med 280:868–875
90. Wyshak G, Frisch RE 1982 Evidence for a secular trend in age of menarche. N Engl J Med 306:1033–1035[Medline]
91. Dann TC, Roberts DF 1993 Menarcheal age in University of Warwick young women. J Biosoc Sci 25:531–538[Medline]
92. Dubrova YE, Kurbatova OL, Kholod ON, Prokhorovskaya VD 1995 Secular growth trend in two generations of the Russian population. Hum Biol 67:755–767[Medline]
93. Sultan C, Paris F, Jeandel C, Attal G, Lumbroso S, Dumas R 2001 L’âge de la puberté et de la ménarche. Rev Int Pediat 32:9–10
94. Marrodan MD, Mesa MS, Arechiga J, Perez-Magdaleno A 2000 Trend in menarcheal age in Spain: rural and urban comparison during a recent period. Ann Hum Biol 27:313–319[CrossRef][Medline]
95. Bodzsar EB, Susanne C 1998 Secular growth change in Europe. Budapest: Eötvö University Press
96. Olesen AW, Jeune B, Boldsen JL 2000 A continuous decline in menarcheal age in Denmark. Ann Hum Biol 27:377–386[CrossRef][Medline]
97. Mau C, Main KM, Hertel T, Holm K, Mosfeldt-Laursen E, Muller J, Skakkebaek N, Juul A 2002 No apparent secular change in age at puberty in Danish girls 1964–1991. Horm Res 58(Suppl 2):84 (Abstract)
98. Lebrethon MC, Bourguignon JP 2000 Management of central isosexual precocity: diagnosis, treatment, outcome. Curr Opin Pediatr 12:394–399[CrossRef][Medline]
99. Klein KO 1999 Precocious puberty: who has it? Who should be treated? J Clin Endocrinol Metab 84:411–414[Free Full Text]
100. Kaplowitz PB, Oberfield SE 1999 Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Pediatrics 104:936–941[Abstract/Free Full Text]
101. Midyett LK, Moore WV, Jacobson JD 2003 Are pubertal changes in girls before age 8 benign? Pediatrics 111:47–51[Abstract/Free Full Text]
102. Pescovitz OH, Comite F, Hench K, Barnes K, McNemar A, Foster C, Kenigsberg D, Loriaux DL, Cutler Jr GB 1986 The NIH experience with precocious puberty: diagnostic subgroups and response to short-term luteinizing hormone releasing hormone analogue therapy. J Pediatr 108:47–54[CrossRef][Medline]
103. Kappy MS, Ganong CS 1994 Advances in the treatment of precocious puberty. Adv Pediatr 41:223–226[Medline]
104. Partsch CJ, Sippell WG 2001 Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update 7:292–302[Abstract/Free Full Text]
105. Thamdrup E 1961 Precocious sexual development: a clinical study of 100 patients. Springfield, IL: Charles C Thomas
106. Wilkins L 1965 The diagnosis and treatment of endocrine disorders in childhood and adolescence. Springfield, IL: Charles C Thomas
107. Sigurjonsdottir TJ, Hayles AB 1968 Precocious puberty. Am J Dis Child 115:309–321[Abstract/Free Full Text]
108. Kaplan SL, Grumbach MM 1990 Pathogenesis of sexual precocity. In: Grumbach M, Sizonenko PC, Aubert ML, eds. Control of the onset of puberty. Baltimore: Williams & Wilkins; 620–662
109. Blanco-Garcia M, Job JC, Chaussain JL, Canlorbe P 1983 Precocious puberty in boys. Arch Fr Pediatr 40:637–642[Medline]
110. Garagorri JM, Chaussain JL, Job JC 1982 [Precocious puberty in girls. Study of 98 cases.] Arch Fr Pediatr 39:605–611 (French)[Medline]
111. Lee PA, Page JG, and the Leuprolide Study Group 1989 Effects of leuprolide in the treatment of central precocious puberty. J Pediatr 114:321–324[CrossRef][Medline]
112. Brauner R, Rappaport R 1990 Pubertés précoces centrales. Semin Hop Paris 66:1782–1787
113. Neely EK 1995 A multicenter trial of depot leuprolide for central precocious puberty. In: Plant TM, Lee PA, eds. The neurobiology of puberty. Bristol, UK: J Endocrinol Ltd; 313–318
114. Palmert MR, Mansfield J, Crowley WF, Grigler JF, Crawford JD, Boepple PA 1999 Is obesity an outcome of gonadotropin-releasing hormone agonist administration? Analysis of growth and body composition in 110 patients with central precocious puberty. J Clin Endocrinol Metab 84:4480–4488[Abstract/Free Full Text]
115. Mul D, Oostdijk W, Otten BJ, Rouwé C, Jansen M, Delemarre-van de Waal HA, Waelkens JJJ, Drop SLS 2000 Final height after gonadotropin releasing hormone agonist treatment for central precocious puberty: the Dutch experience. J Pediatr Endocrinol Metab 13:765–772
116. Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler GB 2001 Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab 86:4711–4716[Abstract/Free Full Text]
117. Lebrethon MC, Bourguignon JP 2001 Central and peripheral isosexual precocious puberty. Curr Opin Endocrinol Diabetes 8:17–22[CrossRef]
118. Adolfsson S, Westphal O 1981 Early pubertal development in girls adopted from Far-Eastern countries. Pediatr Res 15:82 (abstract)
119. Mason P, Narad C, Jester T, Parks J 2000 A survey of growth and development in the internationally adopted child. Pediatr Res 47:209A (abstract)
120. Palmert ML, Boepple PA 2001 Variation in the timing of puberty: clinical spectrum and genetic investigation. J Clin Endocrinol Metab 86:2364–2368[Abstract/Free Full Text]
121. Chicoine JF, Blancquaert I, Chicoine L, Raynault MF 1999 Bilan de santé de 808 chinoises nouvellement adoptées au Québec. Arch Pediatr 6(Suppl 2):544s
122. Gonzalez ER 1982 For puberty that comes too soon, new treatment highly effective. JAMA 248:1149–1152[Abstract/Free Full Text]
123. Mason P, Narad C 2002 Growth and pubertal development in internationally adopted children. Curr Opin Endocrinol Diabetes 9:26–31[CrossRef]
124. Mul D, Oostdijk W, Drop SLS 2002 Early puberty in adopted children. Horm Res 57:1–9
125. Tuvemo T, Gustafsson J, Proos LA 1999 Growth hormone treatment during suppression of early puberty in adopted girls. Acta Paediatr 88:928–932[CrossRef][Medline]
126. Mul D, Oostdijk W, Waelkens JJ, Schulpen TW, Drop SL 2001 Gonadotrophin releasing hormone agonist treatment with or without recombinant human GH in adopted children with early puberty. Clin Endocrinol (Oxf) 55:121–129[CrossRef][Medline]
127. Petri E 1935 Untersuchungen zur Erbbedingtheit der Menarche. Z Morphol Anthropol 33:43–48
128. Fischbein S 1977 Intra-pair similarity in physical growth of monozygotic and of dizygotic twins during puberty. Ann Hum Biol 4:417–430[CrossRef][Medline]
129. Treloar SA, Martin NG 1990 Age at menarche as a fitness trait: nonadditive genetic variance detected in a large twin sample. Am J Hum Genet 47:137–148[Medline]
130. Meyer JM, Eaves LJ, Heath AC, Martin NG 1991 Estimating genetic influences on the age-at-menarche: a survival analysis approach. Am J Med Genet 39:148–154[CrossRef][Medline]
131. Loesch DZ, Hopper JL, Rogucka E, Huggins RM 1995 Timing and genetic rapport between growth in skeletal maturity and height around puberty: similarities and differences between girls and boys. Am J Hum Genet 56:753–759[Medline]
132. Hamilton AS, Mack TM 2003 Puberty and genetic susceptibility to breast cancer in a case-control study in twins. N Engl J Med 348:2313–2322[Abstract/Free Full Text]
133. Stavrou I, Zois C, Ioannidis JP, Tsatsoulis A 2002 Association of polymorphisms of the oestrogen receptor gene with the age of menarche. Hum Reprod 17:1101–1105[Abstract/Free Full Text]
134. Gorai I, Tanaka K, Inada M, Morinaga H, Uchiyama Y, Kikuchi R, Chaki O, Hirahara F 2003 Estrogen-metabolizing gene polymorphisms, but not estrogen receptor- gene polymorphisms, are associated with the onset of menarche in healthy postmenopausal Japanese women. J Clin Endocrinol Metab 88:799–803[Abstract/Free Full Text]
135. Bergman-Jungestrom M, Gentile M, Lundin AC, Wingren S 1999 Association between CYP17 gene polymorphism and risk of breast cancer in young women. Int J Cancer 84:350–353[CrossRef][Medline]
136. Kadlubar FF, Berkowitz GS, Delongchamp RR, Wang C, Green BL, Tang G, Lamba J, Schuetz E, Wolff MS 2003 The CYP3A4*1B variant is related to the onset of puberty, a known risk factor for the development of breast cancer. Cancer Epidemiol Biomarkers Prev 12:327–331[Abstract/Free Full Text]
137. Lai J, Vesprini D, Chu W, Jernstrom H, Narod SA 2001 CYP gene polymorphisms and menarche. Mol Genet Metab 74:449–457[CrossRef][Medline]
138. McEwen B, Alves SE 1999 Estrogen actions in the central nervous system. Endocr Rev 20:279–307[Abstract/Free Full Text]
139. Herbison AE 1998 Multimodal influence of estrogen upon gonadotropin-releasing hormone neurons. Endocr Rev 19:302–330[Abstract/Free Full Text]
140. Ibanez L, Ong KK, Mongan N, Jaaskelainen J, Marcos MV, Hughes IA, De Zegher F, Dunger DB 2003 Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism. J Clin Endocrinol Metab 88:3333–3338[Abstract/Free Full Text]
141. Ojeda SR, Ma YJ, Dziedzic B, Prevot V 2000 Astrocyte-neuron signaling and the onset of female puberty. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 41–57
142. Ito PK 1942 Comparative biometrical study of physique of Japanese women born and reared under different environments. Hum Biol 14:279–351
143. Danker-Hopfe H, Delibalta K 1990 Menarcheal age of Turkish girls in Bremen. Anthropol Anz 48:1–14[Medline]
144. Johnson DE, Miller LC, Iverson S, Thomas W, Franchino B, Dole K, Kiernan MT, Georgieff MK, Hostetter MK 1992 The health of children adopted from Romania. JAMA 268:3446–3451[Abstract/Free Full Text]
145. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS 1993 Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938–941[CrossRef][Medline]
146. Ibanez L, Potau N, Francois I, de Zegher F 1998 Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 83:3558–3562[Abstract/Free Full Text]
147. Francois I, de Zegher F, Spiessens C, D’Hooghe T, Vanderschueren DI 1997 Low birth weight and subsequent male subfertility. Pediatr Res 42:899–901[Medline]
148. Silver HK 1964 Asymmetry, short stature, and variations in sexual development. Am J Dis Child 107:495–515[Abstract/Free Full Text]
149. Marks LJ, Bergeson PS 1977 The Silver-Russell syndrome. Am J Dis Child 131:447–451[Abstract/Free Full Text]
150. Tomkins DJ, Roux AF, Waye J, Freeman VC, Cox DW, Whelan DT 1996 Maternal uniparental isodisomy of human chromosome 14 associated with a paternal t(13q14q) and precocious puberty. Eur J Hum Genet 4:153–159[Medline]
151. Fokstuen S, Ginsburg C, Zachmann M, Schinzel A 1999 Maternal uniparental disomy 14 as a cause of intrauterine growth retardation and early onset of puberty. J Pediatr 134:689–695[CrossRef][Medline]
152. Cooper C, Kuh D, Egger P, Wadsworth M, Barker D 1996 Childhood growth and age at menarche. Br J Obstet Gynaecol 103:814–817[Medline]
153. Ibanez L, Ferrer A, Marcos MV, Hierro FR, de Zegher F 2000 Early puberty: rapid progression and reduced final height in girls with low birth weight. Pediatrics 106:E72 (Abstract)
154. Lazar L, Pollack U, Kalter-Leibovici O, Pertzelan A, Phillip M 2002 Persistently short children with IGUR have a distinct pubertal growth pattern. Horm Res 58(Suppl 2):85 (Abstract)
155. Lienhardt A, Carel JC, Preux PM, Coutant R, Chaussain JL 2002 Amplitude of pubertal growth in short stature children with intrauterine growth retardation. Horm Res 57(Suppl 2):88–94
156. Stark O, Peckham CS, Moynihan C 1989 Weight and age at menarche. Arch Dis Child 64:383–387[Abstract/Free Full Text]
157. Adair LS 2001 Size at birth predicts age at menarche. Pediatrics 107:E59
158. Karlberg J 2002 Secular trends in pubertal development. Horm Res 57(Suppl 2):19–30
159. Delemarre-van de Waal HA, van Coeverden SCCM, Engelbregt MJT 2002 Factors affecting onset of puberty. Horm Res 57(Suppl 2):15–18
160. Engelbregt MJ, Houdijk ME, Popp-Snijders C, Delemarre-van de Waal HA 2000 The effects of intra-uterine growth retardation and postnatal undernutrition on onset of puberty in male and female rats. Pediatr Res 48:803–807[Medline]
161. Proos LA, Hofvander Y, Wennqvist K, Tuvemo T 1992 A longitudinal study on anthropometric and clinical development of Indian children adopted in Sweden. I. Clinical and anthropometric condition at arrival. Ups J Med Sci 97:79–92[Medline]
162. Proos LA, Karlberg J, Hofvander Y, Tuvemo T 1993 Pubertal linear growth of Indian girls adopted in Sweden. Acta Paediatr 82:641–644[Medline]
163. Krstevska-Konstantinova M, Craen M, Beckers D, Dooms L, Heinrichs C, Maes M, De Schepper J, Du Caju M, Thiry-Counson G, Bourguignon JP 1998 Growth pattern in idiopathic central precocious puberty: a comparison between Belgian native and adopted girls. Horm Res 50(Suppl 3):130 (Abstract)
164. Frisch RE, Revelle R 1970 Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Science 169:397–399[Abstract/Free Full Text]
165. Frisch RE, Revelle R 1971 Height and weight at menarche and a hypothesis of menarche. Arch Dis Child 46:695–701
166. Frisch RE, Revelle R, Cook S 1973 Components of weight at menarche and the initiation of the adolescent growth spurt in girls: estimated total water, lean body weight and fat. Hum Biol 45:469–483[Medline]
167. Apter D, Viinikka L, Vihko R 1978 Hormonal pattern of adolescent menstrual cycles. J Clin Endocrinol Metab 47:944–954[Abstract/Free Full Text]
168. Van der Spuy ZM 1985 Nutrition and reproduction. Clin Obstet Gynaecol 12:579–604[Medline]
169. Williams NI, Helmreich DL, Parfitt DB, Caston-Balderrama A, Cameron JL 2001 Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. J Clin Endocrinol Metab 86:5184–5185[Abstract/Free Full Text]
170. Clavel-Chapelon F, E3N-EPIC (European Prospective Investigation into Cancer) Group 2002 Evolution of age at menarche and at onset of regular cycling in a large cohort of French women. Hum Reprod 17:228–232[Abstract/Free Full Text]
171. Arslanian SA, Witchel SF 2002 Polycystic ovary syndrome in adolescents: is there an epidemic? Curr Opin Endocrinol Diabetes 9:32–42[CrossRef]
172. Abbott DH, Dumesic DA, Franks S 2002 Developmental origin of polycystic ovary syndrome—a hypothesis. J Endocrinol 174:1–5[Abstract]
173. Moisan J, Meyer F, Gingras S 1990 A nested case-control study of the correlates of early menarche. Am J Epidemiol 132:953–961[Abstract/Free Full Text]
174. Merzenich H, Boeing H, Wahrendorf J 1993 Dietary fat and sports activity as determinants for age at menarche. Am J Epidemiol 138:217–224[Abstract/Free Full Text]
175. Adair LS, Gordon-Larsen P 2001 Maturational timing and overweight prevalence in US adolescent girls. Am J Public Health 91:642–644[Abstract]
176. Garn SM, La Velle M, Pilkington JJ 1983 Comparisons of fatness in premenarcheal and postmenarcheal girls of the same age. J Pediatr 103:328–331[CrossRef][Medline]
177. Vizmanos B, Marti-Henneberg C 2000 Puberty begins with a characteristic subcutaneous body fat mass in each sex. Eur J Clin Nutr 54:203–208[CrossRef][Medline]
178. Legro RS, Lin HM, Demers LM, Lloyd T 2000 Rapid maturation of the reproductive axis during perimenarche independent of body composition. J Clin Endocrinol Metab 85:1021–1025[Abstract/Free Full Text]
179. Jaruratanasirikul S, Mo-suwan L, Lebel L 1997 Growth pattern and age at menarche of obese girls in a transitional society. J Pediatr Endocrinol Metab 10:487–490[Medline]
180. Wang Y 2002 Is obesity associated with early sexual maturation? A comparison of the association in American boys vs. girls. Pediatrics 110:903–910[Abstract/Free Full Text]
181. Sherman B, Wallace R, Bean J, Schlabaugh L 1981 Relationship of body weight to menarcheal and menopausal age: implications for breast cancer risk. J Clin Endocrinol Metab 52:488–493[Abstract/Free Full Text]
182. van Lenthe FJ, Kemper CG, van Mechelen W 1996 Rapid maturation in adolescence results in greater obesity in adulthood: the Amsterdam growth and health study. Am J Clin Nutr 64:18–24[Abstract/Free Full Text]
183. Qing H, Karlberg J 2001 BMI in childhood and its association with height gain, timing of puberty, and final height. Pediatr Res 49:244–251[Medline]
184. Davison KK, Susman EJ, Birch LL 2003 Percent body fat at age 5 predicts earlier pubertal development among girls at age 9. Pediatrics 111:815–821[Abstract/Free Full Text]
185. Wong WW, Copeland KC, Hergenroeder AC, Hill RB, Stuff JE, Ellis KJ 1999 Serum concentrations of insulin, insulin-like growth factor-I, and insulin-like growth factor binding proteins are different between white and African American girls. J Pediatr 135:296–300[CrossRef][Medline]
186. Gower BA, Higgins PB 2003 Energy balance, body composition, and puberty in children and adolescents: importance of ethnicity. Curr Opin Endocrinol Diabetes 10:9–22[CrossRef]
187. Kaplowitz PB, Slora EJ, Wasserman RC, Pedlow SE, Herman-Giddens ME 2001 Earlier onset of puberty in girls: relation to increased body mass index and race. Pediatrics 108:347–353[Abstract/Free Full Text]
188. Koprowski C, Ross RK, Mack WJ, Henderson BE, Bernstein L 1999 Diet, body size and menarche in a multiethnic cohort. Br J Cancer 79:1907–1911[CrossRef][Medline]
189. Berkey CS, Gardner JD, Frazier AL, Colditz GA 2000 Relation of childhood diet and body size to menarche and adolescent growth in girls. Am J Epidemiol 152:446–452[Abstract/Free Full Text]
190. Soriguer FJ, Gonzalez-Romero S, Esteva I, Garcia-Arnes JA, Tinahones F, Ruiz de Adana MS, Olveira G, Mancha I, Vazques F 1995 Does the intake of nuts and seeds alter the appearance of menarche? Acta Obstet Gynecol Scand 74:455–461[Medline]
191. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg B, Gustafsson JA 1998 Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor ß. Endocrinology 139:4252–4263[Abstract/Free Full Text]
192. McGarvey C, Cates PS, Brooks AN, Swanson IA, Milligan SR, Coen CW, O’Byrne KT 2001 Phytoestrogens and gonadotropin-releasing hormone pulse generator activity and pituitary luteinizing hormone release in the rat. Endocrinology 142:1202–1208[Abstract/Free Full Text]
193. Mazur W, Adlercreutz H 2000 Overview of naturally occurring endocrine-active substances in the human diet in relation to human health. Nutrition 16:654–658[CrossRef][Medline]
194. Adlercreutz H, Bannwart C, Wahala K, Mäkelä T, Brunow G, Hase T, Arosemena PJ, Kellis JTJ, Vickery LE 1993 Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J Steroid Biochem Mol Biol 44:147–153[CrossRef][Medline]
195. Mäkelä S, Poutanen M, Kostian ML, Lehtimäki N, Strauss L, Santti R, Vihko R 1998 Inhibition of 17ß-hydroxysteroid oxidoreductase by flavonoids in breast and prostate cancer cells. Proc Soc Exp Biol Med 217:310–316[CrossRef][Medline]
196. Krazeisen A, Breitling R, Moller G, Adamski J 2001 Phytoestrogens inhibit human 17ß-hydroxysteroid dehydrogenase type 5. Mol Cell Endocrinol 171:151–162[CrossRef][Medline]
197. Mäkelä SI, Pylkkänen LH, Santti RS, Adlercreutz H 1995 Dietary soybean may be antiestrogenic in male mice. J Nutr 125:437–445
198. Krstevska-Konstantinova M, Craen M, Beckers D, Dooms L, Heinrichs C, Bourguignon JP 1999 Precocious puberty in adopted and non-adopted foreign girls moving to Belgium: a role for environmental factors independent of recovery from deprivation. Horm Res 51(Suppl 2):71 (Abstract)
199. Kulin HE, Bwibo N, Mutie D, Santner SJ 1982 The effect of chronic childhood malnutrition on pubertal growth and development. Am J Clin Nutr 36:527–536[Abstract/Free Full Text]
200. Proos LA 1993 Anthropometry in adolescence—secular trends, adoption, ethnic and environmental differences. Horm Res 39(Suppl 3):18–24
201. de Onis M, Dasgupta P, Saha S, Sengupta D, Blössner M 2001 The National Center for Health statistics reference and the growth of Indian adolescent boys. Am J Clin Nutr 74:248–253[Abstract/Free Full Text]
202. de Onis M, Blössner M 2000 Prevalence and trends of overweight among preschool children in developing countries. Am J Clin Nutr 72:1032–1039[Abstract/Free Full Text]
203. Bourguignon JP, Lebrethon MC, Gérard A, Purnelle G, Vandersmissen E, Parent AS, Yamanaka C 2000 Amino acid neurotransmission and early ontogeny of pulsatile GnRH secretion from the rat hypothalamus. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 119–129
204. Foster DL, Nagatani S 1999 Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty. Biol Reprod 60:205–215[Abstract/Free Full Text]
205. Hileman SM, Pierroz DD, Flier JS 2000 Leptin, nutrition, and reproduction: timing is everything. J Clin Endocrinol Metab 85:804–807[Free Full Text]
206. Barker-Gibb ML, Sahu A, Pohl CR, Plant TM 2002 Elevating circulating leptin in prepubertal male rhesus monkeys (Macaca mulatta) does not elicit precocious gonadotropin-releasing hormone release, assessed indirectly. J Clin Endocrinol Metab 87:4976–4983[Abstract/Free Full Text]
207. Farooqi IS, O’Rahilly S 2000 Human congenital leptin deficiency: the role of leptin in the onset of puberty. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 363–369
208. Kalra SP, Pu S, Horvath TL, Kalra PS 2000 Leptin and NPY regulation of GnRH secretion and energy homeostasis. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 317–327
209. Lebrethon MC, Vandersmissen E, Gérard A, Parent AS, Junien JL, Bourguignon JP 2000 Leptin and neuropeptide Y stimulation of pulsatile GnRH secretion in vitro through distinct mechanisms. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 329–337
210. Pierroz DD, Gruaz-Gumowski NM, Lalaoui M, Blum WF, Aubert ML 2000 Leptin and NPY regulation of sexual maturation in the rat. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 339–349
211. Palmert MR, Radovick S, Boepple PA 1998 Leptin levels in children with central precocious puberty. J Clin Endocrinol Metab 83:2260–2265[Abstract/Free Full Text]
212. Heger S, Partsch CJ, Peter M, Blum WF, Kiess W, Sippell WG 1999 Serum leptin levels in patients with progressive central precocious puberty. Pediatr Res 46:71–75[Medline]
213. Horvath TL, Diano S, Sotonyi P, Heiman M, Tschöp M 2001 Minireview: Ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 142:4163–4169[Abstract/Free Full Text]
214. Lebrethon MC, Gérard A, Bourguignon JP 2002 Prepubertal acceleration of pulsatile GnRH secretion in vitro by Ghrelin. Horm Res 58(Suppl 2):19 (Abstract)
215. d’Allèves V, Gruaz-Gumowski NM, Aubert ML 2000 The GH-IGF-I axis in sexual maturation: the rat paradigm. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 59–69
216. Wilson ME, Suter KJ 2000 The GH-IGF-I axis in sexual maturation: the monkey paradigm. In: Bourguignon JP, Plant TM, eds. The onset of puberty in perspective. Amsterdam: Elsevier Science; 71–83
217. Bucholtz DC, Vidwans NM, Herbosa CG, Schillo KK, Foster DL 1996 Metabolic interfaces between growth and reproduction. V. Pulsatile luteinizing hormone secretion is dependent on glucose availability. Endocrinology 137:601–607[Abstract]
218. Schreihofer DA, Renda F, Cameron JL 1996 Feeding-induced stimulation of luteinizing hormone secretion in male rhesus monkeys is not dependent on a rise in blood glucose concentration. Endocrinology 137:3770–3776[Abstract]
219. Cameron JL 1997 Search for the signal that conveys metabolic status to the reproductive axis. Curr Opin Endocrinol Diabetes 4:158–163
220. Roemmich JN, Li X, Rogol AD, Rissman EF 1997 Food availability affects neural estrogen receptor immunoreactivity in prepubertal mice. Endocrinology 138:5366–5373[Abstract/Free Full Text]
221. Hileman SM, Lubbers LS, Jansen HT, Lehman MN 1999 Changes in hypothalamic estrogen receptor-containing cell numbers in response to feed restriction in the female lamb. Neuroendocrinology 69:430–437[CrossRef][Medline]
222. Zhu YS, Dellovade TL, Pfaff DW 1997 Interactions between hormonal and environmental signals on hypothalamic neurons: molecular mechanisms signaling environmental events. Trends Endocrinol Metab 8:111–115
223. Rosner W 1990 The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev 11:80–91[Abstract/Free Full Text]
224. Pascal N, Amouzou EK, Sanni A, Namour F, Abdelmouttaleb I, Vidailhet M, Gueant JL 2002 Serum concentrations of sex hormone binding globulin are elevated in kwashiorkor and anorexia nervosa but not in marasmus. Am J Clin Nutr 76:239–244[Abstract/Free Full Text]
225. Van den Berghe G, de Zegher F, Bouillon R 1998 Clinical review: Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 83:1827–1834[Free Full Text]
226. Chrousos GP 1992 The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267:1244–1252[Abstract/Free Full Text]
227. Theintz GE, Howald H, Allemann Y, Sizonenko PC 1989 Growth and pubertal development of young female gymnasts and swimmers: a correlation with parental data. Int J Sports Med 10:87–91[Medline]
228. Georgopoulos N, Markou K, Theodoropoulou A, Paraskevopoulou P, Varaki L, Kazantzi Z, Leglise M, Vagenakis AG 1999 Growth and pubertal development in elite female rhythmic gymnasts. J Clin Endocrinol Metab 84:4525–4530[Abstract/Free Full Text]
229. Tahirovié HF 1998 Menarchal age and the stress of war: an example from Bosnia. Eur J Pediatr 157:978–980[CrossRef][Medline]
230. Prebeg Z, Bralic I 2000 Changes in menarcheal age in girls exposed to war conditions. Am J Hum Biol 12:503–508
231. Wilson DC, Sutherland I 1950 Age at menarche. Br Med J 1:1267[Free Full Text]
232. Schreihofer DA, Parfitt DB, Cameron JL 1993 Suppression of luteinizing hormone secretion during short-term fasting in male rhesus monkeys: the role of metabolic vs. stress signals. Endocrinology 132:1881–1889[Abstract/Free Full Text]
233. Pacak K, Palkovits M 2001 Stressor specificity of central neuroendocrine responses: implications for stress-related disorders. Endocr Rev 22:502–548[Abstract/Free Full Text]
234. Rivest S, Rivier C 1995 The role of corticotropin-releasing factor and interleukin-1 in the regulation of neurons controlling reproductive functions. Endocr Rev 16:177–199[Abstract/Free Full Text]
235. Belsky J, Steinberg L, Draper P 1991 Childhood experience, interpersonal development and reproductive strategy: an evolutionary theory of socialization. Child Dev 62:647–670[CrossRef][Medline]
236. Wierson M, Long PJ, Forehand RL 1993 Toward a new understanding of early menarche: the role of environmental stress in pubertal timing. Adolescence 28:913–924[Medline]
237. Saar E, Shalev C, Dalal I, Sod-Moriah UA 1988 Age at menarche: the influence of environmental conditions. Int J Biometeorol 32:33–35[CrossRef][Medline]
238. Ellis RWB 1950 Age of puberty in tropics. Br Med J 1:85–89
239. Levine VE 1953 Studies in physiological anthropology: III. Age of onset of menstruation of Alaska Eskimos. Am J Phys Anthropol 11:252
240. Zacharias L, Wurtman RJ 1969 Blindness and menarche. Obstet Gynecol 33:603–608[Medline]
241. Magee K, Basinska J, Quarrington B, Stancer HC 1970 Blindness and menarche. Life Sci 9:7–12[CrossRef][Medline]
242. Bojlen K, Bentzon MW 1974 Seasonal variation in the occurrence of menarche. Dan Med Bull 21:161–168[Medline]
243. Albright DL, Voda AM, Smolensky MH, Hsi BP, Decker M 1990 Seasonal characteristics of and age at menarche. Prog Clin Biol Res 341A:709–720[Medline]
244. Cohen P 1993 Month at menarche: a re-evaluation of the seasonal hypothesis. Ann Hum Biol 20:198–202[Medline]
245. Rojansky N, Brzezinski A, Schenker JG 1992 Seasonality in human reproduction: an update. Hum Reprod 7:735–745[Abstract/Free Full Text]
246. Vanecek J 1999 Inhibitory effect of melatonin on GnRH-induced LH release. Rev Reprod 4:67–72[Abstract]
247. Esquifino AI, Villanua MA, Agrasal C 1987 Effect of neonatal melatonin administration on sexual development in the rat. J Steroid Biochem 27:1089–1093[CrossRef][Medline]
248. Villanua MA, Agrasal C, Esquifino AI 1989 Neonatal melatonin administration advances rat vaginal opening and disrupts estrous cyclicity and estrogen-dependent regulatory mechanisms of luteinizing hormone and prolactin. J Pineal Res 7:165–174[Medline]
249. Silman RE, Leone RM, Hooper RJ, Preece MA 1979 Melatonin, the pineal gland and human puberty. Nature 282:301–303[CrossRef][Medline]
250. Cavallo A, Ritschel WA 1996 Pharmacokinetics of melatonin in human sexual maturation. J Clin Endocrinol Metab 81:1882–1886[Abstract]
251. Salti R, Galluzzi F, Bindi G, Perfetto F, Tarquini R, Halberg F, Cornélissen G 2000 Nocturnal melatonin patterns in children. J Clin Endocrinol Metab 85:2137–2144[Abstract/Free Full Text]
252. Waldhauser F, Boepple PA, Schemper M, Mansfield MJ, Crowley Jr WF 1991 Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children. J Clin Endocrinol Metab 73:793–796[Abstract/Free Full Text]
253. Puig-Domingo M, Webb SM, Serrano J, Peinado MA, Corcoy R, Ruscalleda J, Reiter RJ, de Leiva A 1992 Melatonin-related hypogonadotropic hypogonadism. N Engl J Med 327:1356–1359[Medline]
254. Luboshitzky R, Lavi S, Thuma I, Lavie P 1995 Increased nocturnal melatonin secretion in male patients with hypogonadotropic hypogonadism and delayed puberty. J Clin Endocrinol Metab 80:2144–2148[Abstract]
255. Marshall E 1993 Search for a killer: focus shifts from fat to hormones. Science 259:618–621[Free Full Text]
256. Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette Jr LJ, Jegou B, Jensen TK, Jouannet P, Keiding N, Leffers H, McLachlan JA, Meyer O, Muller J, Rajpert-De Meyts E, Scheike T, Sharpe R, Sumpter J, Skakkebaek NE 1996 Male reproductive health and environmental xenoestrogens. Environ Health Perspect 104(Suppl 4):741–803
257. Guillette Jr LJ 2000 Contaminant-induced endocrine disruption in wildlife. Growth Hormone IGF Res 10(Suppl B):45–50
258. Skakkebaek NE, Rajpert-De Meyts E, Main KM 2001 Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 16:972–978[Abstract/Free Full Text]
259. Snedeker SM 2001 Pesticides and breast cancer risk: a review of DDT, DDE, and dieldrin. Environ Health Perspect 109(Suppl 1):35–47
260. Key T, Reeves G 1994 Organochlorines in the environment and breast cancer. Br Med J 308:1520–1521[Free Full Text]
261. Clark, EJ, Norris DO, Jones RE 1998 Interactions of gonadal steroids and pesticides (DDT, DDE) on gonadal duct in larval tiger salamanders, Ambystoma tigrinum. Gen Comp Endocrinol 109:94–105[CrossRef][Medline]
262. Kelce WR, Stone CR, Laws SC, Gray LE, Kemppainen JA, Wilson EM 1995 Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist. Nature 375:581–585[CrossRef][Medline]
263. Sharpe RM, Skakkebaek NE 1993 Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 341:1392–1395[CrossRef][Medline]
264. McLachlan JA 2001 Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocr Rev 22:319–341[Abstract/Free Full Text]
265. Cohn BA, Cirillo PM, Wolff MS, Schwingl PJ, Cohen RD, Sholtz RI, Ferrara A, Christianson RE, van den Berg BJ, Siiteri PK 2003 DDT and DDE exposure in mothers and time to pregnancy in daughters. Lancet 361:2205–2206[CrossRef][Medline]
266. Herbst AL, Ulfelder H, Poskanzer DC 1971 Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878–881
267. Parent AS, Krstevska-Konstantinova M, Matagne V, Gérard A, Lebrethon MC, Charlier C, Bourguignon JP, the Belgian Study Group for Paediatric Endocrinology 2001 Endocrine disrupter contribution to sexual precocity: suggestive detection of pesticide derivatives in patients immigrant to Belgium and estradiol stimulation of GnRH pulsatility in rat hypothalamus. Pediatr Res 49:139A (abstract)[Medline]
268. Selevan SG, Rice DC, Hogan KA, Euling SY, Pfahles-Hutchens A, Bethel J 2003 Blood lead concentration and delayed puberty in girls. N Engl J Med 348:1527–1536[Abstract/Free Full Text]
269. Wu T, Buck GM, Mendola P Blood lead levels and sexual maturation in US girls: the Third National Health and Nutrition Examination Survey, 1988–1994. Environ Health Perspect 111:737–741
270. Pescovitz OH, Comite F, Cassorla F, Dwyer AJ, Poth MA, Sperling MA, Hench K, McNemar A, Skerda M, Loriaux DL 1984 True precocious puberty complicating congenital adrenal hyperplasia: treatment with a luteinizing hormone-releasing hormone analog. J Clin Endocrinol Metab 58:857–861[Abstract/Free Full Text]
271. Hochberg Z, Schechter J, Benderly A, Leiberman E, Rosler A 1985 Growth and pubertal development in patients with congenital adrenal hyperplasia due to 11-ß-hydroxylase deficiency. Am J Dis Child 139:771–776[Abstract/Free Full Text]
272. Kukuvitis A, Matte C, Polychronakos C 1995 Central precocious puberty following feminizing right ovarian granulosa cell tumor. Horm Res 44:268–270[Medline]
273. Pasquino AM, Tebaldi L, Cives C, Maciocci M, Boscherini B 1987 Precocious puberty in the McCune Albright syndrome. Acta Paediatr Scand 76:841–844[Medline]
274. Boepple PA, Frisch LS, Wierman ME, Hoffman WH, Crowley Jr WF 1992 The natural history of autonomous gonadal function, adrenarche and central puberty in gonadotropin-independent precocious puberty. J Clin Endocrinol Metab 75:1550–1555[Abstract]
275. Wickman S, Dunkel L 2001 Inhibition of P450 aromatase enhances gonadotropin secretion in early and mid pubertal boys: evidence for a pituitary site of action of endogenous estradiol. J Clin Endocrinol Metab 86:4887–4894[Abstract/Free Full Text]
276. Gore AC 2002 Organochlorine pesticides directly regulate gonadotropin-releasing hormone gene expression and biosynthesis in the GT1–7 hypothalamic cell line. Mol Cell Endocrinol 192:157–170[CrossRef][Medline]
277. Atanassova N, McKinnell C, Turner KJ, Walker M, Fisher JS, Morley M, Millar MR, Groome NP, Sharpe RM 2000 Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: evidence for stimulatory effects of low estrogen levels. Endocrinology 141:3898–3907[Abstract/Free Full Text]
278. Saenz de Rodriguez CA, Bongiovanni AM, Conde de Borrego L 1985 An epidemic of precocious development in Puerto Rican children. J Pediatr 107:393–396[CrossRef][Medline]
279. Guarneri MP, Russo G, Sgaramella P, Peroni P, Chiumello G 2001 Epidemic of breast enlargement in a school population: twenty years of follow up. Pediatr Res 49(Suppl):148A (abstract)
280. Den Hond E, Roels HA, Hoppenbrouwers K, Nawrot T, Thijs L, Vandermeulen C, Winneke G, Vanderschueren D, Staessen JA 2002 Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek’s hypothesis revisited. Environ Health Perspect 110:771–776[Medline]

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				A M Bau, A Ernert, L Schenk, S Wiegand, P Martus, A Gruters, and H Krude Is there a further acceleration in the age at onset of menarche? A cross-sectional study in 1840 school children focusing on age and bodyweight at the onset of menarche Eur. J. Endocrinol., January 1, 2009; 160(1): 107 - 113. [Abstract] [Full Text] [PDF]

				Z. K. Z. Gajdos, J. L. Butler, K. D. Henderson, C. He, P. J. Supelak, M. Egyud, A. Price, D. Reich, P. E. Clayton, L. Le Marchand, et al. Association Studies of Common Variants in 10 Hypogonadotropic Hypogonadism Genes with Age at Menarche J. Clin. Endocrinol. Metab., November 1, 2008; 93(11): 4290 - 4298. [Abstract] [Full Text] [PDF]

				T. Chevalley, J.-P. Bonjour, S. Ferrari, and R. Rizzoli Influence of Age at Menarche on Forearm Bone Microstructure in Healthy Young Women J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2594 - 2601. [Abstract] [Full Text] [PDF]

				J.-C. Carel and J. Leger Precocious Puberty N. Engl. J. Med., May 29, 2008; 358(22): 2366 - 2377. [Full Text] [PDF]

				J. O. Sanders, J. G. Khoury, S. Kishan, R. H. Browne, J. F. Mooney III, K. D. Arnold, S. J. McConnell, J. A. Bauman, and D. N. Finegold Predicting Scoliosis Progression from Skeletal Maturity: A Simplified Classification During Adolescence J. Bone Joint Surg. Am., March 1, 2008; 90(3): 540 - 553. [Abstract] [Full Text] [PDF]

				G. Rasier, A.-S. Parent, A. Gerard, R. Denooz, M.-C. Lebrethon, C. Charlier, and J.-P. Bourguignon Mechanisms of Interaction of Endocrine-Disrupting Chemicals with Glutamate-Evoked Secretion of Gonadotropin-Releasing Hormone Toxicol. Sci., March 1, 2008; 102(1): 33 - 41. [Abstract] [Full Text] [PDF]

				E. L. Dempster, I. Burcescu, K. Wigg, E. Kiss, I. Baji, J. Gadoros, Z. Tamas, J. L. Kennedy, A. Vetro, M. Kovacs, et al. Evidence of an Association Between the Vasopressin V1b Receptor Gene (AVPR1B) and Childhood-Onset Mood Disorders Arch Gen Psychiatry, October 1, 2007; 64(10): 1189 - 1195. [Abstract] [Full Text] [PDF]

				G. Rasier, A.-S. Parent, A. Gerard, M.-C. Lebrethon, and J.-P. Bourguignon Early Maturation of Gonadotropin-Releasing Hormone Secretion and Sexual Precocity after Exposure of Infant Female Rats to Estradiol or Dichlorodiphenyltrichloroethane Biol Reprod, October 1, 2007; 77(4): 734 - 742. [Abstract] [Full Text] [PDF]

				H. Niinikoski, H. Lagstrom, E. Jokinen, M. Siltala, T. Ronnemaa, J. Viikari, O. T. Raitakari, A. Jula, J. Marniemi, K. Nanto-Salonen, et al. Impact of Repeated Dietary Counseling Between Infancy and 14 Years of Age on Dietary Intakes and Serum Lipids and Lipoproteins: The STRIP Study Circulation, August 28, 2007; 116(9): 1032 - 1040. [Abstract] [Full Text] [PDF]

				O. V. Martin, J. N. Lester, N. Voulvoulis, and A. R. Boobis Human Health and Endocrine Disruption: A Simple Multicriteria Framework for the Qualitative Assessment of End Point Specific Risks in a Context of Scientific Uncertainty Toxicol. Sci., August 1, 2007; 98(2): 332 - 347. [Abstract] [Full Text] [PDF]

				S.H. Swan, F. Liu, J.W. Overstreet, C. Brazil, and N.E. Skakkebaek Semen quality of fertile US males in relation to their mothers' beef consumption during pregnancy Hum. Reprod., June 1, 2007; 22(6): 1497 - 1502. [Abstract] [Full Text] [PDF]

				L. S. Nield, N. Cakan, and D. Kamat A Practical Approach to Precocious Puberty Clinical Pediatrics, May 1, 2007; 46(4): 299 - 306. [PDF]

				J.-P. Bonjour and T. Chevalley Pubertal Timing, Peak Bone Mass and Fragility Fracture Risk IBMS BoneKEy, February 1, 2007; 4(2): 30 - 48. [Abstract] [Full Text] [PDF]

				J. O. Sanders Maturity Indicators in Spinal Deformity J. Bone Joint Surg. Am., February 1, 2007; 89(suppl_1): 14 - 20. [Full Text] [PDF]

				B. Lee, J. K. Hiney, M. D. Pine, V. K. Srivastava, and W. L. Dees Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action J. Physiol., February 1, 2007; 578(3): 765 - 772. [Abstract] [Full Text] [PDF]

				D. M. Sloboda, R. Hart, D. A. Doherty, C. E. Pennell, and M. Hickey Age at Menarche: Influences of Prenatal and Postnatal Growth J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 46 - 50. [Abstract] [Full Text] [PDF]

				J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, J. Roa, E. Vigo, R. Pineda, R. A. Steiner, E. Aguilar, L. Pinilla, and M. Tena-Sempere Effects of galanin-like peptide on luteinizing hormone secretion in the rat: sexually dimorphic responses and enhanced sensitivity at male puberty Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1281 - E1289. [Abstract] [Full Text] [PDF]

				C. S. Tam, F. de Zegher, S. P. Garnett, L. A. Baur, and C. T. Cowell Opposing Influences of Prenatal and Postnatal Growth on the Timing of Menarche J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4369 - 4373. [Abstract] [Full Text] [PDF]

				J. M. Kindblom, M. Lorentzon, E. Norjavaara, L. Lonn, J. Brandberg, J.-E. Angelhed, A. Hellqvist, S. Nilsson, and C. Ohlsson Pubertal Timing Is an Independent Predictor of Central Adiposity in Young Adult Males: The Gothenburg Osteoporosis and Obesity Determinants Study Diabetes, November 1, 2006; 55(11): 3047 - 3052. [Abstract] [Full Text] [PDF]

				F Domine, A-S Parent, G Rasier, M-C Lebrethon, and J-P Bourguignon Assessment and mechanism of variations in pubertal timing in internationally adopted children: a developmental hypothesis Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S17 - S25. [Abstract] [Full Text] [PDF]

				B. M. Nathan, C. A. Hodges, P. J. Supelak, L. C. Burrage, J. H. Nadeau, and M. R. Palmert A Quantitative Trait Locus on Chromosome 6 Regulates the Onset of Puberty in Mice Endocrinology, November 1, 2006; 147(11): 5132 - 5138. [Abstract] [Full Text] [PDF]

				A. Muir Precocious Puberty Pediatr. Rev., October 1, 2006; 27(10): 373 - 381. [Full Text] [PDF]

				M. Ma, T. Kondo, S. Ban, T. Umemura, N. Kurahashi, M. Takeda, and R. Kishi Exposure of Prepubertal Female Rats to Inhaled Di(2-ethylhexyl)phthalate Affects the Onset of Puberty and Postpubertal Reproductive Functions Toxicol. Sci., September 1, 2006; 93(1): 164 - 171. [Abstract] [Full Text] [PDF]

				C L Acerini and I A Hughes Endocrine disrupting chemicals: a new and emerging public health problem? Arch. Dis. Child., August 1, 2006; 91(8): 633 - 641. [Full Text] [PDF]

				G. Teilmann, C. B. Pedersen, N. E. Skakkebaek, and T. K. Jensen Increased Risk of Precocious Puberty in Internationally Adopted Children in Denmark Pediatrics, August 1, 2006; 118(2): e391 - e399. [Abstract] [Full Text] [PDF]

				L. Aksglaede, A. Juul, H. Leffers, N. E. Skakkebaek, and A.-M. Andersson The sensitivity of the child to sex steroids: possible impact of exogenous estrogens Hum. Reprod. Update, July 1, 2006; 12(4): 341 - 349. [Abstract] [Full Text] [PDF]

				L. Ibanez, C. Valls, K. Ong, D. B. Dunger, and F. de Zegher Metformin Therapy during Puberty Delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height: A Randomized Study in Low-Birth-Weight Girls with Early-Normal Onset of Puberty J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2068 - 2073. [Abstract] [Full Text] [PDF]

				H I Brunner, A Bishnoi, A C Barron, L J Houk, A Ware, Y Farhey, A B Mongey, C F Strife, T B Graham, and M H Passo Disease outcomes and ovarian function of childhood-onset systemic lupus erythematosus Lupus, April 1, 2006; 15(4): 198 - 206. [Abstract] [PDF]

				R. T. Loder, T. Starnes, G. Dikos, and D. D. Aronsson Demographic Predictors of Severity of Stable Slipped Capital Femoral Epiphyses J. Bone Joint Surg. Am., January 1, 2006; 88(1): 97 - 105. [Abstract] [Full Text] [PDF]

				B. J. Crowe, L. T. M. Rekers-Mombarg, K. Robling, A. M. Wolka, G. B. Cutler Jr., J. M., and Wit for the European Idiopathic Short Stature Grou Effect of Growth Hormone Dose on Bone Maturation and Puberty in Children with Idiopathic Short Stature J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 169 - 175. [Abstract] [Full Text] [PDF]

				M. B Pierce and D. A Leon Age at menarche and adult BMI in the Aberdeen Children of the 1950s Cohort Study Am. J. Clinical Nutrition, October 1, 2005; 82(4): 733 - 739. [Abstract] [Full Text] [PDF]

				J. M. Castellano, V. M. Navarro, R. Fernandez-Fernandez, R. Nogueiras, S. Tovar, J. Roa, M. J. Vazquez, E. Vigo, F. F. Casanueva, E. Aguilar, et al. Changes in Hypothalamic KiSS-1 System and Restoration of Pubertal Activation of the Reproductive Axis by Kisspeptin in Undernutrition Endocrinology, September 1, 2005; 146(9): 3917 - 3925. [Abstract] [Full Text] [PDF]

				C. L. Eckhardt, C. Suchindran, P. Gordon-Larsen, and L. S. Adair The Association between Diet and Height in the Postinfancy Period Changes with Age and Socioeconomic Status in Filipino Youths J. Nutr., September 1, 2005; 135(9): 2192 - 2198. [Abstract] [Full Text] [PDF]

				F. J P Ebling The neuroendocrine timing of puberty Reproduction, June 1, 2005; 129(6): 675 - 683. [Abstract] [Full Text] [PDF]

				M. Pine, B. Lee, R. Dearth, J. K. Hiney, and W. L. Dees Manganese Acts Centrally to Stimulate Luteinizing Hormone Secretion: A Potential Influence on Female Pubertal Development Toxicol. Sci., June 1, 2005; 85(2): 880 - 885. [Abstract] [Full Text] [PDF]

				R. K. Semple, J. C. Achermann, J. Ellery, I. S. Farooqi, F. E. Karet, R. G. Stanhope, S. O'Rahilly, and S. A. Aparicio Two Novel Missense Mutations in G Protein-Coupled Receptor 54 in a Patient with Hypogonadotropic Hypogonadism J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1849 - 1855. [Abstract] [Full Text] [PDF]

				M. Denham, L. M. Schell, G. Deane, M. V. Gallo, J. Ravenscroft, A. P. DeCaprio, and and the Akwesasne Task Force on the Environment Relationship of Lead, Mercury, Mirex, Dichlorodiphenyldichloroethylene, Hexachlorobenzene, and Polychlorinated Biphenyls to Timing of Menarche Among Akwesasne Mohawk Girls Pediatrics, February 1, 2005; 115(2): e127 - e134. [Abstract] [Full Text] [PDF]

				V. M Navarro, R Fernandez-Fernandez, J. M Castellano, J Roa, A Mayen, M. L Barreiro, F Gaytan, E Aguilar, L Pinilla, C Dieguez, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54 J. Physiol., December 1, 2004; 561(2): 379 - 386. [Abstract] [Full Text] [PDF]

				V. M. Navarro, J. M. Castellano, R. Fernandez-Fernandez, M. L. Barreiro, J. Roa, J. E. Sanchez-Criado, E. Aguilar, C. Dieguez, L. Pinilla, and M. Tena-Sempere Developmental and Hormonally Regulated Messenger Ribonucleic Acid Expression of KiSS-1 and Its Putative Receptor, GPR54, in Rat Hypothalamus and Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide Endocrinology, October 1, 2004; 145(10): 4565 - 4574. [Abstract] [Full Text] [PDF]

				T. D. Krewson, P. J. Supelak, A. E. Hill, J. B. Singer, E. S. Lander, J. H. Nadeau, and M. R. Palmert Chromosomes 6 and 13 Harbor Genes that Regulate Pubertal Timing in Mouse Chromosome Substitution Strains Endocrinology, October 1, 2004; 145(10): 4447 - 4451. [Abstract] [Full Text] [PDF]

				V. Matagne, G. Rasier, M.-C. Lebrethon, A. Gerard, and J.-P. Bourguignon Estradiol Stimulation of Pulsatile Gonadotropin-Releasing Hormone Secretion in Vitro: Correlation with Perinatal Exposure to Sex Steroids and Induction of Sexual Precocity in Vivo Endocrinology, June 1, 2004; 145(6): 2775 - 2783. [Abstract] [Full Text] [PDF]

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