PEDIATRICS Vol. 111 No. 1 January 2003, pp. 47-51
Are Pubertal Changes in Girls Before Age 8 Benign?
From the Section of Endocrinology, Children’s Mercy Hospital, Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Objective. The Lawson Wilkins Pediatric Endocrine Society recently issued new recommendations for the age at which puberty should be considered precocious, lowering the prevailing standards from 8 years to 7 years for white girls and to 6 years for black girls. The new recommendations were based on a single epidemiologic study that focused on the conditions of premature thelarche and premature adrenarche (both characterized by a single sign of puberty). Although the data were available, the authors did not comment on the low incidence of true precocious puberty (characterized by breast and pubic hair development) in their population. The hypothesis for the present study is that the new recommendations lead to underdiagnosis of endocrine pathology
Methods. Using 29 International Classification of Diseases, Ninth Revision codes for diagnoses known to be associated with precocious puberty, we identified 1570 patient visits to our outpatient pediatric endocrinology clinic of white girls aged 7 to 8 and black girls aged 6 to 8 during a 5-year period
Results. Of the 1570 patient visits, 223 unique patients were identified as having been referred for the sole finding of precocious pubertal development. These 223 patients carried no other endocrine diagnoses. Eleven patients (4.9%) were found to have no true breast buds and no terminally differentiated pubic hair. A total of 105 (47.1%) of 223 patients were found to have 2 signs of puberty, consistent with true precocious puberty according to the conventional guidelines of precocity of 8 years in girls. Overall, 12.3% of patients also had diagnoses of other endocrine conditions that included congenital adrenal hyperplasia, McCune-Albright syndrome, growth hormone deficiency, hypothyroidism, hyperinsulinism, pituitary adenoma, and neurofibromatosis. A total of 35.2% of girls with true precocious puberty exhibited bone ages >3 standard deviations above the mean, indicating markedly diminished growth potential
Conclusions. We conclude that signs of puberty in 6- to 8-year-old girls should not be considered normal or benign. Implementation of the new guidelines for the evaluation of puberty will result in failure to identify conditions that respond to early intervention.
Key Words: precocious puberty • premature thelarche • premature adrenarche • body mass index • polycystic ovary syndrome • hyperinsulinism
Abbreviations: PROS, Pediatric Research in Office Settings • BMI, body mass index • SD, standard deviation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Long-held views on the definition of precocious puberty were challenged by a 1997 study published by the Pediatric Research in Office Settings (PROS) in which 17 077 girls, 3 to 12 years of age, were evaluated for the age of onset of secondary sexual development. The authors of that study concluded that girls "across the United States are developing pubertal characteristics at a younger age than currently used norms."1 On the basis of this study, the Drug and Therapeutics Committee of the Lawson Wilkins’ Pediatric Endocrine Society issued a statement lowering the normal age of puberty to 7 years in white girls and 6 years in black girls.2 The joint committee stated, "In most cases, evaluation of girls with early breast and/or pubic hair development to look for a pathologic etiology of precocious puberty need not be performed for white girls older than 7 years and African-American girls older than 6 year of age."2 This recommendation seemed to us somewhat premature, considering the acknowledged limitations of the study and lack of data on endocrine evaluations performed on girls with early pubertal changes.1 In fact, the revision has led to extensive controversy with a number of pediatric endocrinologists issuing statements contesting the new guidelines. We share the concern expressed by other endocrinologists that liberalizing the definition of "normal" carries with it the risk of overlooking pathology.3,4 In fact, the PROS study included no data as to what percentages of patients younger than 8 years were subsequently referred for complete endocrinologic evaluations and what pathology was found. According to medical standards of care at the time, 22 of their "normal" patients should have been referred for diagnostic evaluations.5
The hypothesis of the current study is that the new guidelines, if followed, will lead to significant underdiagnosis of endocrine conditions. Therefore, it was our primary objective to ascertain the extent of endocrine pathology in girls who are referred to our center for the ages in question: ages 6 to 8 in black girls and 7 to 8 in white girls. A second objective was to identify girls with true precocious puberty (characterized by 2 signs of puberty) in our referral population and to distinguish this entity from the conditions of isolated premature thelarche and isolated premature adrenarche
A recent paper by Kaplowitz et al6 suggested that obesity was linked to the earlier timing of puberty and that patients with obesity were less likely to display pathologic causes for their precocious puberty. Thus, a third objective was to determine whether obese patients were less likely to display additional endocrine pathology
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Population
This study was reviewed by the Institutional Review Board at Children’s Mercy Hospital and received an exempt status. A retrospective chart review was undertaken. Using 29 International Classification of Diseases, Ninth Revision codes for diagnoses known to be associated with precocious puberty, we identified 1570 individual outpatient visits to our pediatric endocrinology clinic by white girls aged 7 to 8 and by black girls aged 6 to 8 from 1996 to 2001. From these visits, 663 unique patients were identified in this age group. A review of these charts identified 223 patients whose only reason for referral was precocious pubertal changes
These 223 girls were seen in our pediatric endocrine clinic, which is based in a large metropolitan children’s hospital, by any of 6 pediatric endocrinologists. Pediatricians or family practitioners referred most patients, but some were self-referred. All of the patients were new to our clinic and had no previously diagnosed endocrine conditions. The diagnosis of true precocious puberty was defined as the presence of both breast and pubic hair development before the age of 8 with a concomitant growth spurt. Tanner staging was assessed on all patients by both visual inspection and palpation. All radiographs for bone age assessment were read by pediatric radiologists at our institution. We requested films on all patients with abnormal bone ages (>2 standard deviations [SD]) to assess accuracy of the bone age reports. Fifty-three of the 83 abnormal bone ages were available and reviewed by a single pediatric endocrinologist: 43 of 53 bone age readings were concordant between the radiologists’ and the endocrinologist’s reviews. Of the 11 that were discordant, 8 readings differed by 6 months or less. No bone age reading was discrepant by more than 1 year. Girls were classified as obese when the body mass index (BMI) was greater than the 95th percentile determined from the Centers for Disease Control and Prevention growth charts for girls in the United States as revised in May 2000
Statistical Analysis
Fisher exact test was used to compare the differences between girls with 2 signs of puberty versus 1 and to compare the differences in pathology between lean girls and obese girls. Fisher exact test also was used to analyze the PROS data for differences between white and black girls with 2 signs of puberty. Z scores for height and weight were derived using computer software based on the revised Centers for Disease Control and Prevention growth charts for girls in the United States. Student t test was used for the comparisons of height and weight, BMI, 
bone ages, and predicted adult height between patients with 2 signs of puberty and those with 1 sign of puberty
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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We compared differences between groups with 1 sign of early sexual development (breast or pubic hair alone) or 2 signs of early sexual development (breast and pubic hair). Of the total 223 patients referred to us, 105 (47%) had evidence of both breast and pubic hair development, 83 (37%) had evidence of pubic hair development alone, and 24 (11%) had only breast development. Eleven girls (5%) were referred for signs of puberty but were found to have no true signs of early sexual development
Clinical findings seen in our population included increased BMI, advanced bone ages, and diminished growth potential. Of the 212 patients found to have signs of puberty, 95 (45%) were obese, with a greater percentage of girls with 2 signs of pubertal development being overweight compared with those with 1 sign of puberty (52 [50%] of 105 vs 36 [34%] of 107; P = .024; Table 1). The majority of girls received a diagnosis of idiopathic pubertal development. However, 1 girl (4%) with early breast development, 13 girls (16%) with pubic hair development, and 12 girls (11%) with both breast and pubic hair development were found to have additional endocrine diagnoses. These diagnoses included neurofibromatosis, McCune-Albright syndrome, growth hormone deficiency, hypothyroidism, congenital adrenal hyperplasia, pituitary microadenoma, and hyperinsulinism (Table 2)
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Patients with 2 signs of pubertal development exhibited the following: 1) significantly greater weight z scores (1.65 + 0.09) compared with patients with either premature thelarche (1.00 + 0.23) or premature adrenarche (1.22 + 0.14; P = .006 and 0.008, respectively; Fig 1), 2) significantly greater height z scores (1.27 + 0.11) compared with patients with either premature thelarche (0.54 + 0.22) or premature adrenarche (0.80 + 0.12; P = .006 and 0.007, respectively; Fig 2), 3) significantly higher BMI (20.67 + 0.35) compared with patients with premature thelarche (18.77 + 0.66; P = .02; Fig 3), 4) bone ages that were significantly more advanced (1.99 + 0.14 years) compared with those of patients with either premature thelarche (1.19 + 0.32 years) or premature adrenarche (0.80 + 0.18 years; P = .02 and <.001, respectively; Fig 4), and 5) a greater loss of final predicted adult height z scores (-1.03 + 0.31) compared with girls with premature adrenarche alone (-0.77 + 0.10; P = .000001; Fig 5)
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Bone ages were advanced up to 5 years above chronological age in girls with 2 signs of puberty. Of girls with 2 signs of puberty, 37 (35%) of 105 girls exhibited bone ages >3 SD above the mean. Eight patients with 2 signs of puberty and 1 patient with premature thelarche exhibited predicted height below 150 cm (4 ft 11 in). No girl with premature adrenarche exhibited a predicted height <150 cm
With regard to endocrine pathology in obese versus nonobese patients, the results revealed that although 45% of patients overall were obese, 81% of girls who had a diagnosis of additional endocrine conditions were obese. Twenty-one of 95 patients who were obese exhibited additional endocrine pathology, whereas only 5 of 117 patients who were not obese displayed additional pathology (P = .0001; odds ratio: 6.3)
We compared black and white girls with the same pubertal changes for differences in BMI, weight z scores, height z scores, bone age, and potential loss in predicted adult height. Black girls in the 6- to 7-year range were excluded, as there were no white girls in that age group. The only difference between the 7- to 8-year-old black and white girls was in the premature adrenarche group when comparing potential loss of adult height. Black girls with premature adrenarche displayed significantly lower height z scores between current height and predicted height based on bone age (z score: -1.06 vs -0.62). The significance of this difference became marginal when adjusted for multiple comparisons
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Our data indicate that pathologic endocrine conditions were present in a subset of patients who were referred to us for precocious pubertal changes occurring at an age defined as normal by the PROS study. Overall, 12.3% of the patients who were referred to our endocrine clinic between the ages of 6 and 8 manifested pathologic explanations for their sexual precocity. These endocrine diagnoses included insulin resistance/hyperinsulinism, congenital adrenal hyperplasia, neurofibromatosis, growth hormone deficiency, hypothyroidism, and McCune-Albright syndrome. It is important to note that the physical findings can be subtle in patients with nonclassical congenital adrenal hyperplasia, subclinical hypothyroidism, forme frustes of McCune-Albright syndrome, or neurofibromatosis. Thus, it is not surprising that these conditions were not previously diagnosed by the referring physicians. That precocious puberty may be the first and/or only recognized manifestation raises the concern that the diagnosis of endocrine disorders might be overlooked if the new guidelines are followed
Perhaps of greater concern than the pathologic diagnoses was the additional finding of advanced bone ages, indicating diminished growth potential in a larger subset of girls. More than one third of girls with 2 signs of puberty exhibited bone ages >3 SD above the mean. A subset of girls who presented with breast development alone also exhibited advanced bone ages. In fact, girls with breast development alone were just as likely to display potential losses in adult height as girls with 2 signs of puberty. This is not surprising, as estrogen is a major factor in progression of skeletal maturation. The finding of loss of adult height potential in girls with isolated premature thelarche underscores the need for individual evaluation by pediatric subspecialists to determine who is at risk for compromise of adult height. If these girls had not been evaluated between the ages and 6 and 8, then it is doubtful that they would have been evaluated later, unless premature menarche occurred, at which time growth potential would have been limited
Our study was based on a referral population and so does not address prevalence of pathology in the general population. One might argue that our referral population has changed since the new guidelines have been in place, with pediatricians referring fewer and more complicated patients. Our analysis does not support this contention. We found that the number of girls who were referred to our clinic for evaluation of early pubertal development did not decrease after publication of the new guidelines
Pediatric endocrinologists have long made the important distinction between the potentially benign conditions of isolated premature thelarche (characterized by breast development alone), premature adrenarche (characterized by pubic hair development alone), and true precocious puberty (characterized by breast and pubic hair development), which carries with it a higher prevalence of significant pathologic conditions to explain the precocious development.7 Although it is important to distinguish true precocious puberty from the partial forms of puberty, our data indicate that almost 16% of girls who presented with only early pubic hair development were found to have additional endocrine diagnoses. Importantly, hyperinsulinism was the most frequent additional endocrine diagnosis in girls who presented with early pubic hair or both. Recent studies have emphasized that premature adrenarche may be the first recognizable sign of the symptom complex identified as polycystic ovary syndrome or the metabolic syndrome (hyperinsulinism, obesity, impaired glucose tolerance, dyslipidemia, cardiovascular disease).8–11 In fact, the number of girls who are at risk for this problem is likely higher in our population than the data suggest, as insulin levels and oral glucose tolerance testing were not routinely done on girls with signs of premature adrenarche in the initial years of our study period. Early recognition and dietary intervention may be beneficial in this subgroup of patients, again underscoring the need for early identification and referral to subspecialists
An editorial by Herman-Giddens et al12 stated, "We question the recommendation that all girls with the sole factor of breast development or pubic hair before 8 and 9 years of age, respectively, have a diagnostic evaluation." In practice, it has not been the standard of care for pediatricians or pediatric endocrinologists to perform extensive evaluations in girls with 1 sign of puberty before the age of 8 or 9. Before the revision in guidelines, standard practice would be to take an appropriate history, perform a thorough physical examination, observe linear growth, and possibly perform simple bone age assessment in girls with single signs of puberty. More extensive studies would be reserved for girls with 2 signs of puberty. Our findings suggest that all girls with any secondary sexual development before 8 years of age deserve at the minimum a bone age assessment and close longitudinal follow-up, especially when one considers that breast and pubic hair development can be asynchronous in the early stages of precocious puberty
A close inspection of the graphs in the original study from the PROS group reveals that only a small percentage of patients exhibited findings of true precocious puberty. It seems that only 2 black girls (1.6%) and 6 white girls (0.4%) aged 6 years to 7 years displayed 2 signs of puberty. Eight black girls (5.9%) and 12 white girls (1.1%) aged 7 to 8 years displayed 2 signs of puberty.1 These calculations are important for 2 reasons. First, assuming a normal distribution of onset of puberty, it calls into question whether a major epidemiologic change in the timing of puberty has occurred at all. This low incidence of true precocious puberty is in line with the PROS finding that the age of menarche has not changed more than a few months since the early 1960s.1,13 Second, our analysis of the PROS data published reveals that there is no statistically significant difference in the incidence of true precocious puberty between white and black girls in the 6- to 7-year age group.1 Thus, the PROS data do not provide a scientific basis for using separate guidelines for black and white girls between the ages of 6 and 7 years
Additional analysis of the data in the original study from the PROS group reveals that of the total of 17 077 girls—55 black girls between the ages of 6 and 8 and 75 white girls between the ages of 7 and 8—exhibited 1 sign of puberty.1 Accordingly, only 130 girls (0.8%) would have required additional evaluation under the prevailing standards of care at the time. The additional evaluation might have been as simple as a bone age assessment or fasting serum insulin and glucose levels. Only 22 girls out of the entire population of 17 077 girls (0.1%) of the ages and races in question would have met the definition of true precocious puberty under the definitions of precocity at the time. Subspecialty referral of 100% of girls with 2 signs of puberty would hardly overwhelm the current health care system, even with the current shortage of pediatric endocrinologists
A recent study by Kaplowitz et al6 suggested that obesity should be considered a causative factor in early puberty and that weight should be taken into account as a mitigating factor when deciding whether to refer patients to search for pathologic causes. Our data do not support this recommendation. Whereas 45% of patients overall were obese, 81% of the girls with additional endocrine diagnoses were obese. This finding suggests that equal attention should be given to obese girls and nonobese girls who present with signs of early pubertal development
The extensive list and complexity of the endocrine conditions associated with precocious sexual development underscores the need for complete evaluation and individualized attention by subspecialists. On the basis of the results of our study, we will continue to recommend referral of any girl who is younger than 8 years and has 2 signs of puberty. We will also continue to recommend (at a minimum) a bone age evaluation on all girls who are younger than 8 years and have even 1 sign of sexual development. The subsequent evaluation and/or referral should be tailored to identify endocrine conditions expected in each subtype of early sexual development
Additional studies in other endocrinology practices will help to determine whether a similar degree of pathology exists in other referral centers. Our study underscores the hazard in revising population guidelines based on a single epidemiologic study. Strict adherence to the new guidelines and exclusion from endocrine evaluations of girls who are aged 6 to 8 and have secondary sexual development will lead to underdiagnosis and undertreatment in this age group
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ACKNOWLEDGMENTS |
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We thank Steve Simon, PhD, for expertise and assistance in the statistical analysis for this article
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FOOTNOTES |
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Received for publication Jan 2, 2002; Accepted May 24, 2002.
Reprint requests to (J.D.J.) Section of Endocrinology, Children’s Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108. E-mail: jjacobson{at}cmh.edu
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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