The developmental changes in plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase.

Schiebinger, Rick J.; Albertson, Barry D.; Cassorla, Fernando; Bowyer, D W; Geelhoed, Glenn W.; Cutler, Gordon B.; Loriaux, D. Lynn

doi:10.1172/jci110132

Cited by 130 publications

(38 citation statements)

References 31 publications

(34 reference statements)

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“…Consequently, in the physiological situation, almost all androgen synthesis proceeds through DHEA, which, therefore, is considered the principal human androgen precursor. An early study employing human adrenal microsomes from individuals of different ages found lower CYP17A1 activities in individuals aged 2 months to 9 years than in adults (131) and subsequently has been cited as evidence for a characteristic increase in 17,20 lyase activity at the time of adrenarche. However, current in vivo evidence points towards a much earlier onset of adrenal androgen secretion at around age 3 years (17).…”

Section: Adrenal Steroidogenesis During Adrenarchementioning

confidence: 99%

Premature adrenarche: novel lessons from early onset androgen excess

Idkowiak

Lavery

Dhir

et al. 2011

European Journal of Endocrinology

110

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Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.

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Section: Adrenal Steroidogenesis During Adrenarchementioning

confidence: 99%

Premature adrenarche: novel lessons from early onset androgen excess

Idkowiak

Lavery

Dhir

et al. 2011

European Journal of Endocrinology

110

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“…Recently, the expression patterns of the steroid-metabolizing enzymes within the human fetal, neonatal and adult adrenal have been studied, giving some insight into adrenal androgen production. Of the two enzymes needed for DHEA synthesis, CYP11A (cholesterol sidechain cleavage) and CYP17 (17 -hydroxylase, 17,20-lyase), only the 17,20 lyase activity of CYP17 appears to alter its activity as the adrenal initiates DHEA production at adrenarche (Schiebinger et al 1981, Suzuki et al 2000. There also appears to be a negative correlation between the enzyme type II 3 -hydroxysteroid dehydrogenase (HSD3B2) and DHEA(S) production (Doody et al 1990, Endoh et al 1996, Gell et al 1998a, Suzuki et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Src tyrosine kinase stimulates adrenal androgen production

Sirianni

Carr²,

Andò

et al. 2003

Journal of Molecular Endocrinology

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A unique characteristic of the primate adrenal is the ability to produce 19-carbon steroids, often called the adrenal androgens. Although it is clear that the major human adrenal androgens, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S), are produced almost solely in the adrenal reticularis, the mechanisms regulating production are poorly understood. Herein, we tested the hypothesis that the Src family of tyrosine kinases are involved in the regulation of adrenal androgen production. The NCI-H295R human adrenal cell line and primary human adrenal cells in culture were used to study adrenal androgen production and expression of enzymes involved in steroidogenesis. To examine the role of Src tyrosine kinase, cells were treated with PP2, a specific Src inhibitor. Alternatively, adrenal cells were transfected with an expression vector containing a dominant-negative form of Src. PP2 treatment inhibited basal cortisol production while significantly increasing the production of DHEA and DHEA-S (together referred to as DHEA(S)) in both adrenal cell models. The effect of PP2 on steroidogenesis occurred along with a rapid induction of steroidogenic acute regulatory (StAR) protein synthesis as revealed by Western analysis. Treatment with PP2 also increased mRNA levels for StAR, and cholesterol side-chain cleavage (CYP11A) and 17α-hydroxylase/17,20-lyase (CYP17) enzymes. Treatment of adrenal cells with the cAMP agonist dibutyryladenosine cyclic monophosphate (dbcAMP), stimulated the production of cortisol and DHEA(S). However, treatment of adrenal cells with a combination of PP2 and dbcAMP enhanced the production of DHEA(S) while inhibiting cortisol production. During dbcAMP treatment PP2 was able to augment the expression of CYP17 and to inhibit the induction of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) levels. Increasing the CYP17 to HSD3B2 ratio is likely to promote the use of steroid precursors for the production of DHEA(S) and not for cortisol. Taken together these data suggest that the inhibition of Src tyrosine kinases causes adrenal cells to adopt a reticularis phenotype both by the production of DHEA(S) and by the steroidogenic enzymes expressed.

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“…Some authors have suggested that the increase in adrenal androgen production at adrenarche is due to some maturational change within the adrenal gland itself (11)(12)(13). It has been reported that the zona reticularis, the innermost zone of the adrenal cortex that predominantly secretes adrenal androgens, appears at the time of adrenarche (11).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been suggested that maturational changes in the activities of some adrenal enzymes (17-hydroxylase, 17-20-lyase and the 3b-hydroxysteroid dehydrogenase, D 4-5 isomerase system) may account for alterations in steroidogenesis favouring androgens (13)(14)(15). Alternatively, factors extrinsic to the adrenal may specifically control adrenal androgen biosynthesis and secretionfor example, the putative cortical androgen stimulating hormone.…”

Section: Figurementioning

confidence: 99%

“…The potential endogenous adrenal gland mechanisms regulating adrenal androgen secretion include maturation and zonation of the adrenal gland (11), adrenal blood flow that may expose the inner zone to high concentrations of cortisol (12), and changes in the properties of the adrenal enzymes and their co-factors (13)(14)(15). Alternatively, factors outside the adrenal gland have been proposed, such as prolactin (16), growth hormone (17), insulin (18), sex steroids (19,20) and fragments of the ACTH precursor molecule, pro-opiomelanocortin, such as b-endorphin (21) and joining peptide (21,22).…”

Section: Introductionmentioning

confidence: 99%

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Intra-adrenal factors are not involved in the differential control of cortisol and adrenal androgens in human adrenals

Fearon

Clarke²,

McKenna³

et al. 1998

European Journal of Endocrinology

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The differential control of adrenal androgens and cortisol may be due to intra-adrenal factors, which may be age-or sex-related, or due to extra-adrenal factors, such as circulating hormones. The purpose of this study was to identify any intrinsic differences that may exist in steroidogenic production occurring within adrenals obtained from males and females, and any maturational differences that may evolve with age. Using human adrenals from 48 transplant donors (32 males, 16 females; ages 5-60 years), the influences of age and sex on basal production of and ACTH-stimulated cortisol, androstenedione and dehydroepiandrosterone (DHEA) were examined in freshly prepared adrenal cell suspensions. Basal and ACTH-stimulated cortisol, androstenedione and DHEA production were similar in adrenals from males and females and did not correlate significantly with age when the whole group was examined. When steroidogenesis in male and female adrenals was examined separately against age, a significant correlation was observed only for basal and ACTH-stimulated androstenedione in adrenals from males in the younger age group, 5-30 years (basal: r ¼ 0.84, P ¼ 0.0001; ACTH-stimulated: r ¼ 0.52, P ¼ 0.007). Examination of the relationships between the steroids disclosed that the basal and ACTH-stimulated cortisol/androgen ratios did not correlate significantly with age, but the androstenedione/DHEA ratio showed a significant direct relationship with age in males only (basal: r ¼ 0.53, P ¼ 0.006; ACTH-stimulated: r ¼ 0.5, P=0.01).These data suggest that the influences of sex and age are minor in the modulation of adrenal steroidogenesis and support the concept that extra-adrenal factors dominate in the differential modulation of adrenal androgens and cortisol. The relationship between the androstenedione/ DHEA ratio and increasing age in men is consistent with the recently reported stimulatory effect of testosterone on adrenal steroidogenesis by induction of the conversion of DHEA to androstenedione.

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The developmental changes in plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase.

Cited by 130 publications

References 31 publications

Premature adrenarche: novel lessons from early onset androgen excess

Premature adrenarche: novel lessons from early onset androgen excess

Inhibition of Src tyrosine kinase stimulates adrenal androgen production

Intra-adrenal factors are not involved in the differential control of cortisol and adrenal androgens in human adrenals

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