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*EPINEPHRINE
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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 11 5038-5043
Copyright © 2002 by The Endocrine Society

Original Article

Pubertal and Gender-Related Changes in the Sympathoadrenal System in Healthy Children

Martina Weise, Graeme Eisenhofer and Deborah P. Merke

Developmental Endocrinology Branch (M.W.) and Pediatric and Reproductive Endocrinology Branch (D.P.M.), National Institute of Child Health and Human Development; and The Warren Grant Magnuson Clinical Center (D.P.M.), and Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke (G.E.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Deborah P. Merke, M.D., National Institutes of Health, Building 10, Room 13S260, 10 Center Drive, MSC 1932, Bethesda, Maryland 20892-1932. E-mail: dmerke{at}nih.gov.

Abstract

A critical amount of body fat is necessary for the initiation of puberty, and leptin, an adipocyte-derived hormone, is necessary for pubertal development. The sympathoadrenal system modulates body fat stores and leptin secretion and interacts with adrenocortical androgen production, suggesting a possible role in sexual maturation. We studied sympathetic nerve and adrenomedullary activity at rest in 80 healthy children (ages, 5–17 yr; 37 boys and 43 girls) in relation to age, pubertal stage, gender, physical activity, body mass index, and serum levels of sex steroids, dehydroepiandrosterone sulfate, cortisol, leptin, and insulin.

Plasma concentrations of the adrenomedullary hormone, epinephrine (E), and its metabolite metanephrine (MN), decreased significantly with advancing puberty and were higher in boys than in girls. E and MN correlated significantly and inversely with dehydroepiandrosterone sulfate, estradiol, testosterone, leptin, and insulin. Plasma norepinephrine, which is primarily derived from sympathetic nerve endings, increased significantly with advancing puberty and increasing testosterone levels in boys. Stepwise multiple regression analysis revealed that E was best predicted by pubertal stage and leptin, and MN by estradiol and leptin.

Our data suggest that sympathoadrenal hormones may play a role in the complex process of sexual maturation. Further studies are needed to investigate a possible modulatory role of the adrenal medulla in the body weight-related timing of adrenarche and/or gonadarche.

PUBERTY IS THE developmental process of sexual maturation. Adrenarche, the adrenal component of pubertal maturation, typically occurs earlier than gonadarche, the maturation of the hypothalamic-pituitary-gonadal axis. A progressive increase in dehydroepiandrosterone sulfate (DHEA-S) heralds the onset of adrenarche, whereas a progressive increase in testosterone (T) in males and estradiol (E2) in females is characteristic of gonadarche. Factors that trigger the onset of adrenarche and gonadarche are unknown. However, a critical amount of body fat and adequate nutrition are essential. Leptin, an adipocyte-derived hormone, has also been implicated as playing a role in both adrenarche (1) and gonadarche (2, 3, 4).

The sympathetic nerve and adrenomedullary systems play an important role in circulatory homeostasis and energy metabolism. Plasma norepinephrine (NE) is predominantly derived from sympathetic nerve endings in which it acts as a neurotransmitter. In contrast, epinephrine (E) is synthesized in the adrenal medulla from its precursor NE. Catechol-O-methyltransferase converts NE and E to their respective inactive metabolites, normetanephrine (NMN) and metanephrine (MN). The adrenal medulla is especially rich in this enzyme and produces 91% of circulating MN and 23% of circulating NMN (5). E stimulates metabolic rate in humans (6) and reduces leptin production and secretion in adipose tissue (7, 8, 9). Obese individuals have been found to have elevated leptin concentrations, decreased E secretion, and impaired ß-adrenergic responses (10, 11, 12, 13, 14, 15, 16), suggesting that the adrenomedullary system plays an important role in the regulation of adipose tissue.

The two adrenal systems, the cortisol- and androgen- producing cortex and the catecholamine (E and NE)-producing medulla, are related ontogenetically, anatomically, and functionally (17, 18, 19), suggesting that adrenomedullary function might be linked to the process of adrenarche. Moreover, the dose-dependent inhibition of adrenomedullary catecholamine secretion in response to adrenal androgens (20, 21) and the presence of ß2-receptors on cortical cells (22) suggest interdependence of E and DHEA production and/or secretion in the adrenal gland. Therefore, adrenomedullary function might play a role in the weight-related timing of adrenarche. However, a comprehensive evaluation of plasma catecholamines or metanephrines (MN and NMN) has not been performed in children, and their role in sexual maturation is unknown.

We measured baseline plasma concentrations of E, NE, MN, and NMN in healthy boys and girls under standardized conditions and assessed their relationship to age, gender, pubertal stage, physical activity, body mass index (BMI)-SD score, and plasma hormones that are thought to play an important role in pubertal development or body fat regulation.

Materials and Methods

Subjects

Eighty healthy children (43 girls and 37 boys; ages, 5–17 yr) were studied. All children had a normal physical examination, normal screening laboratory tests (blood count, sedimentation rate, blood glucose, electrolytes, liver and kidney function tests) and no history of chronic disease, and none were taking medication. Pubertal stage was assessed by physical examination by a single investigator (M.W.), according to the criteria of Tanner for breast development in females (23) and according to a modified genital staging method based on the average volume of both testes in males (24). Specifically, testicular volumes less than 4 ml were defined as stage 1; 4 ml to less than 8 ml, stage 2; 8 ml to less than 12 ml, stage 3; 12 ml to less than 15 ml, stage 4; and at least 15 ml, stage 5. Physical activity level was derived from information on organized sports and free time activities (sweat-inducing exercise of at least 30-min duration; level 1, less than one time per week; level 2, one to two times per week; level 3, three to four times per week; level 4, five or more times per week). The study was approved by the institutional review board at the National Institute of Child Health and Human Development. Written informed consent was obtained from a parent of each subject, and each child gave assent.

Study protocol

Subjects were instructed to abstain from caffeinated foods and drinks for at least 24 h and to avoid acetaminophen, which interferes with the NMN assay (25), for at least 5 d before testing. Subjects were evaluated in the morning after a 9-h overnight fast (water permitted), and an indwelling venous cannula was placed in one forearm. Subsequently, subjects rested in the supine position in a quiet environment for 20 min until blood was drawn from the indwelling line for determination of E, NE, MN, NMN, glucose, insulin, leptin, cortisol, DHEA-S, E2, and T. The blood for measurement of catecholamines and metanephrines was drawn into a prechilled 10-ml heparinized tube and immediately spun; the plasma was frozen at -70 C until assayed.

Assays

Plasma E, NE, MN, and NMN were determined by liquid chromatography with electrochemical detection (25, 26). The detection limits of the assays were 5–10 pmol/liter. Plasma glucose was measured by glucose hexakinase method at the Clinical Center laboratories at the National Institutes of Health. Serum concentrations of DHEA-S, E2, T, and leptin were measured by RIA (Esoterix Endocrinology, Calabasas Hills, CA). Serum insulin and cortisol were measured using an immunoenzymetric assay (Covance Laboratories, Inc. Vienna, VA).

Statistical analyses

BMI-SD score was determined using anthropometric reference data for U.S. children (27). The Fisher’s exact test was used to compare the percentages of pubertal and prepubertal children between boys and girls. Gender differences were otherwise assessed using the two-tailed t test or Mann-Whitney U test as appropriate. Linear regression analysis and Pearson’s correlation coefficients were used to evaluate the other variables under investigation. Stepwise multiple regression analysis was used to determine the best clinical and hormonal predictors of plasma catecholamines and metanephrines. Serum concentrations of E2, T, insulin, leptin, and cortisol were log-transformed for regression analyses. Significance was accepted at a P value less than 0.05.

Results

There were no significant gender differences in age, pubertal status, or BMI-SD score (Table 1Go). Plasma E, MN, and NMN concentrations were higher in boys than in girls, whereas plasma NE levels did not differ (Table 1Go).


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  		Table 1. Group characteristics and hormone levels

 
Plasma concentrations of the adrenomedullary hormone E and its metabolite MN decreased markedly with increasing age (Table 2Go) and pubertal stage (Fig. 1Go). In contrast, plasma NE, the catecholamine predominantly secreted by sympathetic nerves, increased with advancing age (Table 2Go) and puberty (Fig. 1Go) in boys only. The NE metabolite, NMN, did not change with either age (Table 2Go) or puberty (Fig. 1Go).


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  		Table 2. Correlations between age and sympathoadrenal hormones

 


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  		Figure 1. Pubertal changes of plasma concentrations (mean ± SEM) of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine) in healthy boys (filled bars) and girls (open bars).

 
Levels of the adrenomedullary hormone E and its metabolite MN were strongly and inversely correlated with serum concentrations of DHEA-S, E2, and T in both boys and girls (Fig. 2Go). Conversely, NE correlated positively with T in boys only (r = 0.351; P = 0.03), and NMN did not correlate with any of the measured sex steroids in either gender.



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  		Figure 2. Plasma concentrations of epinephrine and metanephrine in relation to DHEA-S, E2, and T levels in healthy boys (filled circles) and girls (open circles). Lines indicate linear regression for boys (continuous) and girls (dotted).

 
In this population of healthy children, BMI was within the normal age-adjusted range in all except five children. Higher BMI-SD score tended to be associated with lower plasma levels of E and MN (Fig. 3Go). Leptin and insulin levels were inversely correlated with E and MN (Fig. 3Go) but were not correlated with NE or NMN. Fasting insulin and leptin highly correlated with each other and with BMI-SD score in boys and girls (P < 0.001). No correlation was found between E, NE, MN, or NMN and cortisol or glucose concentrations.



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  		Figure 3. Plasma concentrations of epinephrine and metanephrine in relation to BMI-SD score (SDS) and leptin and insulin levels in healthy boys (filled circles) and girls (open circles). Lines indicate linear regression for boys (continuous) and girls (dotted).

 
Resting plasma E, NE, and NMN did not vary significantly with levels of physical activity, but MN, a marker of adrenomedullary stores, increased with physical activity in both boys and girls (boys, r = 0.304, P = 0.06; girls, r = 0.448, P = 0.003). Increased physical activity was associated with lower BMI-SD score in both sexes (boys, r = -0.424, P = 0.009; girls, r = -0.438, P = 0.004). On average, boys were physically more active than girls (Table 1Go).

Multivariate stepwise regression analysis revealed that plasma E concentrations were best predicted by pubertal stage and leptin, plasma MN by E2 and leptin, NE by T, and NMN by gender (Table 3Go). When boys and girls were analyzed separately, results were similar (Table 3Go).


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  		Table 3. Predictors of plasma catecholamines and metanephrines (multivariate stepwise regression analysis)

 
Discussion

Our data demonstrate that plasma levels of catecholamines and metanephrines vary with pubertal development and gender. Our data also support the notion that the adrenal medulla and the sympathetic nervous system represent distinct systems with different actions and functions (28), as suggested by their divergent relationship to age (29, 30, 31), gender (31, 32), and obesity (10, 11, 12, 13).

In our study, plasma levels of the adrenomedullary hormone E and its metabolite MN decreased with advancing age and puberty in both boys and girls. However, boys showed higher plasma levels of E and MN than girls, a finding in agreement with previous studies in adults (31, 32). In contrast, plasma levels of NE, which is primarily derived from sympathetic nerve endings, increased with advancing age and puberty in boys but not girls. The NE metabolite NMN, although higher in boys than girls, did not change during puberty in either gender.

The observed gender and age/puberty related variations of catecholamines and metanephrines might be, at least partially, explained by actions of sex steroids. E2 has been shown to suppress adrenomedullary secretion of E in vitro (33), to decrease basal as well as stress-induced NE and E responses in both men (34) and women (35), and to down-regulate catechol-O-methyltransferase, the enzyme that metabolizes E and NE to MN and NMN, respectively (36). Our findings of strong inverse correlations between plasma E or MN and serum E2 levels in both boys and girls as well as the fact that girls had lower NMN levels than boys despite similar NE concentrations are in accordance with these previous reports.

The relationships between T and catecholamine production, release, and/or metabolism are not clear. Some studies suggested a suppressive effect (37, 38), others a stimulatory effect of E on T secretion (39, 40). Whether T, in turn, influences sympathetic or adrenomedullary function has not been investigated to our knowledge. Under resting conditions, we found plasma E and T levels to be inversely correlated, but E2 rather than T was identified as an independent predictor of E. Thus, T might affect E levels indirectly after aromatization to E2. In contrast, the increase in plasma NE observed in the boys was related to puberty and increasing T levels.

A critical amount of body fat is known to be essential for the onset of puberty, and leptin is an important permissive hormone for pubertal development. E stimulates energy expenditure (6), decreases leptin production and secretion in adipose tissue (7, 8, 9), and stimulates lipolysis (14, 15, 16). However, the role of E in adiposity regulation has not been fully elucidated. Obesity has repeatedly been shown to be associated with reduced baseline and stimulated E levels (10, 11, 12, 13), but whether decreased E is the cause or the consequence of obesity is still under investigation. Obese individuals have been shown to have elevated leptin concentrations and resistance to the lipolytic effects of E (14, 15, 16), suggesting that the adrenomedullary system plays an important role in the regulation of adipose tissue. This view is further supported by the finding of reduced basal and stimulated plasma E levels in normal weight but formerly obese compared with never-obese women (41), the inverse relationship between plasma E levels and serum leptin and/or being overweight in healthy individuals (12, 13, 42), and the association of reduced lipolytic response to E and obesity in patients with Gs deficiency (43).

Obesity is associated not only with high serum levels of leptin and insulin and decreased E secretion but also with accelerated adrenarche (44) and gonadarche (45, 46). In addition, there is good evidence that leptin, as well as insulin, directly stimulates adrenal androgen production (1, 47, 48, 49). Thus, adrenomedullary function might influence the timing of sexual maturation by affecting the fat stores of the body and consequently serum leptin and insulin levels.

The presence of leptin (50, 51) and insulin (47) receptors in the adrenal medulla suggests that these hormones in turn may have a direct modulatory effect on adrenomedullary hormones. However, contradictory results have been published showing either a stimulatory effect (51) or no effect (50) of leptin on E release.

The close inverse relationship between E and DHEA-S levels observed in our study suggests additional modulatory interactions between adrenal androgen production and adrenomedullary function. Although our data cannot prove a causal relationship, several previous findings indicate interdependence of adrenal E and DHEA-S production and/or secretion in the adrenal gland: the anatomical proximity and close intermingling of chromaffin and cortical cells in the human adrenal (19), the innervation of the adrenal cortex by nerve fibers originating in the medulla (52), the presence of ß2-receptors on cortical cells (22), and the rapid dose-dependent inhibition of catecholamine secretion demonstrated in cultured bovine adrenal medulla cells in response to DHEA-S (20) and other adrenal androgens (21).

The possibility exists that age-related changes in the clearance of catecholamines may have contributed to the observed age-related changes in plasma E. Clearance of circulating E is mainly due to uptake by extraneuronal tissue, especially the liver, kidneys, and skeletal muscle (5, 53). Age-related changes in body mass, cardiac output, and/or blood flow to tissues of uptake may influence clearance and thus plasma levels of circulating E. However, we did not find age-related decreases in plasma norepinephrine that paralleled those in E.

Our study is the first report of plasma catecholamine levels in healthy children in relation to pubertal development. Our data suggest that sympathoadrenal hormones may play a role in the complex developmental process of puberty. In particular, the adrenal medulla might have a significant role in linking body weight to the timing of sexual maturation. Adrenomedullary function appears to be tightly linked to sex steroids and leptin, possibly explaining the observed variations in the adrenomedullary hormones with puberty and gender. Further studies are needed to investigate the clinical implications of the observed decrease in adrenomedullary hormone concentrations with pubertal progression and to explore a possible modulatory role of the adrenal medulla in the body weight-related timing of sexual maturation.

Acknowledgments

Footnotes

D.P.M. is a Commissioned Officer in the United States Public Health Service.

Abbreviations: BMI, Body mass index; DHEA-S, dehydroepiandrosterone sulfate; E, epinephrine; E2, estradiol; MN, metanephrine; NE, norepinephrine; NMN, normetanephrine; T, testosterone.

Received April 15, 2002.

Accepted August 6, 2002.

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C. Syme, M. Abrahamowicz, G. T. Leonard, M. Perron, A. Pitiot, X. Qiu, L. Richer, J. Totman, S. Veillette, Y. Xiao, et al.
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C. Hadtstein, E. Wuhl, M. Soergel, K. Witte, F. Schaefer, and the German Study Group for Pediatric Hypertension
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M. Weise, S. L. Mehlinger, B. Drinkard, E. Rawson, E. Charmandari, M. Hiroi, G. Eisenhofer, J. A. Yanovski, G. P. Chrousos, and D. P. Merke
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Defect in Epinephrine Production in Children with Craniopharyngioma: Functional or Organic Origin?
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