Abstract
Premature adrenarche (PA), the early rise in adrenal androgen production leading to prepubertal signs of androgen action, has been connected with adverse metabolic features. The metabolic syndrome is characterized by low-grade inflammation which in turn is associated with increases in circulating proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). We tested the hypothesis that serum concentrations of TNF-α and IL-6 are increased in PA by studying 73 children with PA and 98 age- and gender-matched controls. Serum TNF-α and IL-6 concentrations were measured using a multiplex bead array. The subjects were genotyped for the TNF-α gene -308 G > A polymorphism (known to affect TNF-α gene transcription), and genotype–phenotype associations were studied. The mean serum TNF-α concentration was higher in the PA than control children (20.4 vs. 18.4 pg/ml, P = 0.048), whereas there was no significant difference in the mean serum IL-6 concentrations between the study groups. The difference in TNF-α was not explained by excess body weight in the PA subjects as the difference remained significant after BMI-adjustment (P = 0.038). In the PA group, TNF-α concentration was not associated with metabolic-endocrine features, but high IL-6 was associated with lower birth weight. There was no difference in the genotype distribution of the TNF-α gene -308 G > A polymorphism between the PA and control groups. In conclusion, PA was associated with increased serum TNF-α concentrations which, unexpectedly, were not connected with BMI or insulin resistance. The TNF-α gene -308 G > A polymorphism does not seem to be associated with the development of PA.
Highlights
Premature adrenarche (PA) refers to the clinical condition in which earlier than normal increase in the production of adrenal androgens leads to clinical signs of androgen action before the age of 8 years in a girl or 9 years in a boy, and androgen producing tumors, congenital adrenal hyperplasia, and precocious puberty are excluded (Voutilainen et al, 1983; Ibanez et al, 2000; Utriainen et al, 2009a)
Serum TNF-a and interleukin 6 (IL-6) concentrations Serum TNF-α concentrations were significantly higher in the PA than control children (Table 1)
Serum TNF-α and IL-6 concentrations were interconnected in both groups (r = 0.90, P < 0.001 and r = 0.75, P < 0.001 in the PA and control group, respectively)
Summary
Premature adrenarche (PA) refers to the clinical condition in which earlier than normal increase in the production of adrenal androgens leads to clinical signs of androgen action before the age of 8 years in a girl or 9 years in a boy, and androgen producing tumors, congenital adrenal hyperplasia, and precocious puberty are excluded (Voutilainen et al, 1983; Ibanez et al, 2000; Utriainen et al, 2009a). Low-grade inflammation is generally accepted to be involved in the pathogenetic process of the metabolic syndrome and cardiovascular diseases (reviewed in Antuna-Puente et al, 2008; Rizvi, 2009). This connection may be caused by increased number of macrophages in the adipose tissue (Weisberg et al, 2003). Adipose tissue macrophages are characterized by overproduction of proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) (Antuna-Puente et al, 2008). Excess central fat mass has been observed in girls with PA (Ibanez et al, 2003)
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