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In Boys with Abnormal Developmental Tempo, Maturation of the Skeleton and the Hypothalamic-Pituitary-Gonadal Axis Remains Synchronous

Developmental Endocrinology Branch (A.F.-C., E.W.L., K.M.B., M.C., J.B.) and Warren Grant Magnuson Clinical Center and the Pediatric Reproductive Endocrinology Branch (D.P.M.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Eli Lilly and Company (G.B.C.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Armando Flor-Cisneros, M.D., Building 10 RM 10N262, 10 Center Drive MSC 1862, Bethesda, Maryland 20892-1862. E-mail: flora{at}mail.nih.gov.

	Abstract

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The primary mechanism that initiates puberty is unknown. One possible clue is that pubertal maturation often parallels skeletal maturation. Conditions that delay skeletal maturation also tend to delay the onset of puberty, whereas conditions that accelerate skeletal maturation tend to hasten the onset of puberty. To examine this relationship, we studied boys with congenital adrenal hyperplasia (n = 13) and familial male-limited precocious puberty (n = 22), two conditions that accelerate maturational tempo, and boys with idiopathic short stature (n = 18) in which maturational tempo is sometimes delayed.

In all three conditions, the onset of central puberty generally occurred at an abnormal chronological age but a normal bone age. Boys with the greatest skeletal advancement began central puberty at the earliest age, whereas boys with the greatest skeletal delay began puberty at the latest age. Furthermore, the magnitude of the skeletal advancement or delay matched the magnitude of the pubertal advancement or delay. This synchrony between skeletal maturation and hypothalamic-pituitary-gonadal axis maturation was observed among patients within each condition and also between conditions. In contrast, the maturation of the hypothalamic-pituitary-gonadal axis did not remain synchronous with other maturational processes including weight, height, or body mass index.

We conclude that in boys with abnormal developmental tempo, maturation of the skeleton and the hypothalamic-pituitary-gonadal axis remains synchronous. This synchrony is consistent with the hypothesis that in boys, skeletal maturation influences hypothalamic-pituitary-gonadal axis maturation.

	Introduction

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THE TRANSFORMATION OF a child into an adult involves not only an increase in size but also a qualitative maturation in form and function of many organ systems. The skeleton, for example, forms initially out of cartilage and is subsequently converted into bone tissue (1). This process concludes with epiphyseal fusion. Skeletal maturation can be assessed radiologically and quantified as a bone age. A second important maturational process involves the hypothalamic-pituitary-gonadal (HPG) axis. During childhood, GnRH secretion is suppressed, but during the adolescent years, this suppression is released, initiating puberty. The mechanisms immediately responsible for this suppression and subsequent activation involve neuronal input to the hypothalamic GnRH pulse generator (2, 3). However, the primary timing mechanism that initiates the activation and thus triggers puberty is unknown (4).

In some circumstances, there appears to be a temporal correlation between skeletal maturation and HPG axis maturation. Conditions that delay maturation of the skeleton also tend to delay maturation of the HPG axis. Such conditions include chronic disease, malnutrition, hypothyroidism, constitutional delay, and GH deficiency (5, 6, 7, 8, 9, 10). Conversely, conditions that accelerate skeletal maturation, such as peripheral precocious puberty, obesity, and Marfan syndrome, also accelerate maturation of the HPG axis, causing central precocious puberty (11, 12, 13, 14, 15). A general concordance between the rates of different maturational processes was observed by Tanner (16), who used the term tempo to refer to the overall pace of somatic maturation.

The mechanism responsible for this temporal correlation between skeletal maturation and HPG axis maturation is unknown (2), in part because the correlation has not been carefully characterized. Although informal observations suggest that the two systems tend to be regulated in the same direction, there have been few systematic studies to determine whether the two systems remain truly synchronous in disorders that affect maturational tempo. Lack of synchrony would argue against a direct causal link between the two systems.

To explore these issues, we asked whether maturation of the skeleton and the HPG axis remain synchronous in boys with conditions that affect the tempo of maturation. We therefore studied boys with congenital adrenal hyperplasia and familial male-limited precocious puberty, two conditions that accelerate maturational tempo, and boys with idiopathic short stature in which maturational tempo is sometimes delayed.

	Subjects and Methods

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Subjects

All subjects were participating in one of three ongoing treatment trials, which were approved by the Institutional Review Board of the National Institute of Child Health and Human Development. Informed consent was obtained from a parent of each patient, and assent was obtained from the older children. Subjects were included in the current retrospective analysis if onset of central puberty occurred during the course of the clinical trial. This determination was based on testicular volume and GnRH stimulation testing as defined below.

The 22 subjects with familial male-limited precocious puberty (FMPP) were receiving spironolactone 5.7 mg/kg·d and testolactone 40 mg/kg·d (12). Inclusion criteria for the trial included 1) diagnosis of FMPP, 2) age less than 10 yr, and 3) unfused epiphyses. All boys included in the current analysis had a known mutation in the LH receptor.

The 13 subjects with congenital adrenal hyperplasia (CAH) had been randomly assigned to one of two treatment regimens (17). Nine patients were receiving hydrocortisone (12 mg/m²·d) and fludrocortisone (175 µg/d), and four patients were receiving hydrocortisone (8 mg/m²·d), fludrocortisone (230 µg/d), testolactone (40 mg/kg·d), and flutamide (10 mg/kg·d). The inclusion criteria for the trial included 1) diagnosis of classic 21-hydroxylase deficiency and 2) bone age 2–13 yr.

The 18 subjects with idiopathic short stature (ISS) were receiving either GH, 0.074 mg/kg three times per week, or placebo (18). The inclusion criteria for the treatment protocol included 1) chronological age 10–16 yr, 2) bone age 13 yr or less, 3) testicular volume 10 ml or less, 4) proportionate short stature with absolute and/or predicted height -2.5 SD or less, and 5) peak stimulated GH 7 µg/liter or less. Target height, bone age delay, and growth velocity were not part of the inclusion criteria.

Normative data were obtained from the 2000 National Center for Health Statistics study (19). Height age of a subject was defined as the age at which the median height of normal boys was equal to the subject’s height. Weight age and body mass index (BMI) age were defined analogously. Bone age advancement was defined as bone age minus chronological age. Height age advancement, weight age advancement, and BMI age advancement were defined analogously. Pubertal advancement was defined as the normal age of pubertal onset for boys, 12 yr (20) minus chronological age at onset of puberty.

Clinical evaluation

The subjects were evaluated every 6 months, including the following measurements: testicular volume using a Prader orchidometer (21), GnRH test (CAH and FMPP patients only), bone age, morning height (average of at least three measurements) using a Harpenden stadiometer, and weight. LH and FSH were measured by RIA (Covance, Vienna, VA). Bone age was evaluated by observers unaware of the study hypothesis using the method of Greulich and Pyle (22).

In subjects with CAH, the onset of central puberty was defined by either a testicular volume at least 4 ml (in the absence of significant testicular adrenal rest tissue by ultrasound) or a GnRH-stimulation test (peak LH 30 mIU/ml or peak LH/ peak FSH ratio 3.66) (23). In subjects with FMPP (which affects testicular volume directly), onset of central puberty was defined by GnRH testing. In subjects with ISS, GnRH testing was not performed and the onset of central puberty was defined by a testicular volume at least 4 ml.

Statistical analysis

Statistical differences were assessed by one-way ANOVA. Data are expressed as mean ± SD.

	Results

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In subjects with CAH and FMPP, the onset of central puberty occurred at an early chronological age but a normal bone age (Fig. 1). Conversely, in subjects with ISS, the onset of central puberty occurred at a late chronological age but a normal bone age (Fig. 1). Thus, the mean bone age at onset of puberty was similar in FMPP (12.0 yr), CAH (12.8 yr), and ISS (11.9 yr) (Table 1). This synchrony at onset of puberty was not observed for other markers of growth and maturation, including chronological age, height, weight, and BMI. Thus, for example, boys with CAH entered puberty with significantly greater BMI than boys with FMPP or ISS (Table 1).

View larger version (18K): [in this window] [in a new window]   FIG. 1. Comparison of bone age (BA) and chronological age (CA) at onset of central puberty in boys with FMPP (•), CAH (), and ISS ().

Among individuals within each of the three diagnostic categories, there was a positive correlation between the severity of skeletal advancement and the severity of pubertal advancement (Fig. 2). Thus, in CAH and FMPP, subjects with the greatest skeletal advancement tended to have the greatest pubertal advancement (FMPP: r = 0.46, P = 0.03; CAH: r = 0.93, P < 0.001) (Fig. 2, A and B). Conversely, in ISS, subjects with the greatest skeletal delay tended to have the greatest pubertal delay (r = 0.88, P < 0.001) (Fig. 2C).

View larger version (30K): [in this window] [in a new window]   FIG. 2. Correlation between bone age (BA) advancement (BA-chronological age) and pubertal advancement (12 - chronological age) in each diagnostic category: A, FMPP; B, CAH; C, ISS; D, combined.

In contrast, the severity of pubertal advancement or delay did not correlate well with any other maturational markers that we examined (Table 2). The severity of pubertal advance did correlate significantly with the height age advancement for boys with CAH and ISS. However, the height age advancement explained less of the variance in pubertal advancement (CAH: r = 0.59; ISS: r = 0.68) than did bone age advancement (CAH: r = 0.93; ISS: r = 0.88). Furthermore, among boys with FMPP, there was not a significant correlation between height age and pubertal advancement.

	Discussion

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The criteria to determine the onset of central puberty differed among the three diagnostic groups. In boys with CAH, onset of central puberty was defined by either a testicular volume at least 4 ml or by a pubertal response to GnRH analog. In these patients, ultrasound was performed to exclude testicular enlargement due to adrenal rest tissue. Because FMPP causes mild testicular enlargement even in the absence of central puberty (18), the GnRH stimulation test alone was used to determine the onset of central puberty. In ISS, central puberty was defined by testicular volume at least 4 ml, because serial GnRH testing had not been performed. We cannot directly verify whether the testicular volume and GnRH test criteria are equivalent in these patient populations. However, the GnRH test regimen, gonadotropin assays, and LH and FSH concentration criteria were selected because they correlate well with secondary sexual characteristics in normal boys (23).

Height age, weight age, and BMI age, which compare the child with normative data, may not be ideal markers of somatic maturation. For example, a child with familial short stature would have a delayed height age even though his overall maturation may not be delayed. In this case, the percent of his adult height achieved (i.e. his height divided by his eventual adult height) might be a better marker of maturation. However, adult heights were not available for many patients.

We were unable to assess the correlation between skeletal maturation and HPG axis maturation in girls with abnormal developmental tempo. In girls with CAH and with McCune Albright syndrome, we could not identify a reliable criterion for onset of central puberty based on the GnRH-stimulated peak LH levels and/or peak LH/FSH ratio (data not shown). These values varied erratically with age, sometimes alternating from pubertal to prepubertal levels within a single female subject, unlike the gradual increase in gonadotropins seen in boys. Therefore, we do not know whether skeletal maturation and HPG axis maturation remain synchronous in girls.

Our data suggest that in boys, the relationship between HPG axis maturation and bone maturation may be bidirectional. There is already a well established causal connection between these two processes; maturation of the HPG axis increases estrogen concentrations, which in turn accelerate skeletal maturation (Fig. 3, causal relationship 1). This known causal connection could explain a correlation between bone age and achievement of mid-late pubertal stages because progression through puberty causes increasing exposure to sex steroids, maturing the skeleton. However, this causal direction is less likely to explain a correlation between bone age and achievement of pubertal onset. At pubertal onset, sex steroid levels are just beginning to rise (25). The concentrations are probably not high enough and the time of exposure is probably insufficient to significantly advance bone age. Particularly in the boys with CAH and FMPP, the small increase in sex steroids that occurs at the very beginning of central puberty would be minor compared with the sex steroids already present due to the underlying disease. Furthermore, in the boys in FMPP and some of those with CAH, the treatment with an antiandrogen and an aromatase inhibitor would be expected to block much of the effect of sex steroids on the skeleton. Therefore, the association between bone age and pubertal onset observed in the current study suggests that the reverse causal relationship may exist as well; skeletal maturation may influence maturation of the HPG axis (Fig. 3, causal relationship 2).

View larger version (20K): [in this window] [in a new window]   FIG. 3. Diagram of possible causal relationships between skeletal maturation and HPG axis maturation.

Previous studies have suggested a temporal correlation between skeletal maturation and pubertal onset, both in conditions that slow maturational tempo, including chronic disease, malnutrition, hypothyroidism, constitutional delay, and GH deficiency (5, 7, 8, 9, 10), and also in conditions that accelerate maturational tempo, including peripheral precocious puberty (11, 12, 13) and obesity (14). Most of these previous studies suggest that skeletal and HPG axis maturation tend to be regulated in the same direction but did not determine whether or not the two systems remain truly synchronous. However, for GH deficiency, this relationship has been well studied, and synchrony does appear to be maintained (10). In contrast, in normal children, the onset of puberty reportedly does not show a stronger association with bone age than with chronological age (26). This reported lack of association between skeletal advancement and pubertal advancement in normal children, if correct, argues against a direct causal link between the two systems (26). However, in the study supporting that conclusion, the onset of puberty was determined using photographs rather than by direct inspection, palpation of breast tissue, measurement of testicular volume, or biochemical testing, and the mathematical analysis assessing the association was limited.

The observed synchrony between skeletal and HPG axis maturation may provide an important clue to the mechanisms that regulate the onset of puberty. During childhood, the reproductive axis is quiescent because the hypothalamic GnRH pulse generator is suppressed by neuronal input. During adolescence, this suppression is released, initiating puberty. The regulation of GnRH secretion may involve inhibitory neurotransmitters, including -aminobutyric-acid (GABA), neuropeptide Y (NPY), and opioids, and stimulatory neurotransmitters, including glutamate and norepinephrine (2, 3, 27). In addition, glial-neuronal interactions involving TGF-, neuroregulins, and prostaglandin E2 may regulate GnRH secretion (28, 29).

The primary timing mechanism that initiates the activation of GnRH secretion and thus triggers puberty is unknown (4). Two alternative general hypotheses have been proposed. First, the timing mechanism might reside within the central nervous system, perhaps involving the neurotransmitters and glial-neuronal interactions mentioned above. A second possibility is that the pubertal clock might reside outside the nervous system.

Somatic maturation could cause a change (either an increase or a decrease) in the concentration of a circulating factor that regulates neuronal/glial input to the hypothalamic pulse generator. Thus, puberty could be initiated when the concentration of this factor reaches a threshold. For example, it has been hypothesized that the accumulation of adipose tissue causes an increase in leptin concentration, which then initiates puberty (30). However, studies in rodents (31), rhesus monkeys (32), and humans (33) suggest that although inadequate leptin does inhibit the reproductive axis, leptin does not appear to be involved in the clock that controls the onset of puberty. In our study, pubertal onset did not correlate closely with BMI.

The observed synchrony in boys between skeletal maturation and pubertal maturation raises the possibility that skeletal maturation might provide the biological clock timing the onset of puberty. Plant et al. (3, 34) have speculated that a substance secreted by the immature skeleton might be responsible for imposing the prepubertal hiatus in pulsatile GnRH release. With increasing age, skeletal maturation might cause a decrease in the production of this factor, thereby releasing the inhibition of the HPG axis. For example, if the factor were produced by growth cartilage, the gradual replacement of this cartilage by bone tissue might cause a decline in circulating levels of the factor. This possible interaction between the skeleton and the HPG axis might provide a mechanism that delays reproduction until somatic growth is complete. A link between these systems might have been particularly advantageous when nutritional intake was uncertain, causing variability in the chronological age at which adult stature was achieved.

Our findings also provide a useful clinical rule. In boys with peripheral precocious puberty, evaluation and treatment for secondary central puberty should be considered when the bone age approaches the normal age of pubertal onset. Secondary central puberty can exacerbate the abnormalities of growth, skeletal maturation, behavior, and secondary sexual characteristics, and thus evaluation and treatment of this supervening event may be clinically important (35).

We conclude that in conditions that alter developmental tempo in boys, the maturation of the skeleton and the HPG axis remains synchronous. This synchrony is maintained in boys with CAH and FMPP, conditions that accelerate maturational tempo, and in boys with ISS, in which maturational tempo may be delayed. This maintenance of synchrony is consistent with the hypothesis that skeletal maturation might regulate HPG axis maturation.

	Footnotes

 
D.P.M. and J.B. are commissioned officers in the United States Public Health Service.

Abbreviations: BMI, Body mass index; CAH, congenital adrenal hyperplasia; FMPP, familial male-limited precocious puberty; HPG, hypothalamic-pituitary-gonadal; ISS, idiopathic short stature.

Received December 12, 2002.

Accepted October 15, 2003.

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