Adrenarche and Puberty in Children with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Abstract

There have been only a few studies on adrenarche in girls with classic congenital adrenal hyperplasia (CAH) showing that dehydroepiandrosterone sulfate (DHEAS) levels did not rise at the physiological age of adrenarche. Objective: Longitudinal analysis of serum DHEAS levels and Tanner stages in CAH children. Design: We studied 98 CAH patients (52 females), aged between 1 month and 18.0 years. All patients had genetically proven classic CAH and received steroid substitution therapy. Results: Serum DHEAS levels did not differ between CAH children and healthy children from the age of 1 year until 5–6 years. Beginning at the age of 7–8 years, there was a continuous but blunted increase in DHEAS levels in CAH boys and girls compared to healthy children. There was no correlation of DHEAS levels with the genotype, glucocorticoid dosage, auxological data, or quality of metabolic control. Pubarche (PH2) as well as gonadarche (G2) and thelarche (B2) occurred significantly earlier in CAH boys and girls than in the reference group, but timing of menarche was normal. Conclusions: Pubarche and adrenarche are dissociated in classic CAH: earlier pubarche, gonadarche and thelarche, respectively, in both sexes contrast with the absence of typical adrenarche.

Hormonal circadian rhythms in patients with congenital adrenal hyperplasia: identifying optimal monitoring times and novel disease biomarkers

“…In addition, DHEA levels did not correlate with any of the other measured hormones. Low DHEA has previously been described in patients with classic CAH 31, 32 . Our data support the notion that DHEA is not solely regulated by ACTH in CAH patients, but low levels may be due to abnormal adrenal gland development as patients with 21-hydroxylase deficiency have been shown to have lack of zonation with extensive intermingling of adrenocortical and adrenomedullary cells 7, 33 .…”

“…Our data support the notion that DHEA is not solely regulated by ACTH in CAH patients, but low levels may be due to abnormal adrenal gland development as patients with 21-hydroxylase deficiency have been shown to have lack of zonation with extensive intermingling of adrenocortical and adrenomedullary cells 7, 33 . Low intra-adrenal cortisol in CAH patients also may result in low DHEA production 31, 34 .…”

Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency

“…An important strength of our study is the inclusion of both males and females with classic 21OHD. Although clinical stigmata of adrenal androgen excess can be subtle in males, they suffer from sexual precocity 12, 32–34 and infertility 4–6 , similar to females. The inclusion of males in both our comparison of 21OHD with unaffected controls, as well as in our AV analysis, allowed us to conclude that the major source of 11oxC19 steroids is the adrenal gland.…”

“…Furthermore, reliable biomarkers that accurately distinguish adrenal from gonadal androgen synthesis are lacking, and as a consequence, biochemical targets of disease control are not well defined, especially after the onset of puberty 8, 9 . Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), the most abundant 19-carbon (C 19 ) steroids produced by the adrenal glands 10 , are disproportionally suppressed by glucocorticoid treatment and are not good indicators of hyperandrogenism in classic 21OHD 11, 12 . Similarly, there is no good correlation between the routinely measured androgens, androstenedione (AD) and, in women, testosterone (T), and clinical evidence of androgen excess in 21OHD patients 13, 14 , suggesting that other unrecognized androgens might be produced by the adrenal gland.…”

Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21‐hydroxylase deficiency

“…Interestingly, children with classic CAH fail to have a physiological rise in DHEAS levels during childhood, effectively accounting for absence of a typical adrenarche . This is likely due to a development defect in the adrenal gland .…”