Health Articles

 

Microsoft word - review. normal and premature adrenarche. manuscript alicia belgorosky.doc

NORMAL AND PREMATURE ADRENARCHE
Alicia Belgorosky; María Sonia Baquedano; Gabriela Guercio; Marco A. Servicio de Endocrinologia, Hospital de Pediatría Garrahan, Buenos Aires,
1. INTRODUCTION
Adrenarche occurs only in higher primates, typical y at 6-8 y of age in humans, when the innermost layer of adrenal cortex, the zona reticularis, develops. This is an event of posnatal sexual maturation in which there is an increase in the secretion of adrenal androgens, mainly dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), not accompanied by an increase in cortisol secretion (1). The zona reticularis (ZR) is in theory the morphological equivalent of the fetal zone of adrenal cortex. The primate adrenal produces large amounts of DHEA and DHEAS during fetal development, which decrease rapidly after birth, since the fetal zone virtual y disappears during the first few months of postnatal life (2-6). Thereafter, longitudinal studies have shown a progressive increase in serum concentration of DHEA and DHEAS in healthy boys and girls, beginning at 6 to 8 years of age, roughly in paral el with an increase in skeletal age (7-15). However, in contrast to the latter proposal, adrenarche might begin earlier in childhood, as suggested by studies performed in healthy children measuring DHEA, as wel as the DHEA metabolites in 24-h urine samples (16). Even though adrenarche might be a multifactorial event, the main process regulating the production of adrenal androgens continues to represent one of the most intriguing mysteries in adrenal functional differentiation. Although a non-ACTH pituitary factor, stimulating adrenal androgen production has been proposed to work in concert with ACTH (17) today, no circulating factor has been found that might initiate this process. Moreover, according to recent studies, it has been suggested that the increment of adrenal androgen production is associated to the enlargement of ZR (18-21). In addition, the regulation of adrenal steroidogenesis in zona reticularis is a complex process, since adrenarche requires both the acquisition of 17, 20-lyase activity of P450c17 and a decrease of 3beta HSD expression (18-20,22-27). Several factors, such us the IGF system, insulin, the immune system, and also a possible modulatory role of the adrenal medul a have been proposed, among others, to be involved in the regulation of the functional differentiation of adrenal ZR cel s (18-28). However, the mechanism of adult adrenal cortex remodeling and zonation has to be elucidated. The fact that adrenarche is confined to higher–order primates indicates that this phenomenon is a relatively recent evolutionary development. Even thought the importance of the fetal production of DHEA and DHEAS is related to their role as substrates for the massive rise in estrogens biosynthesis during gestation (29), the significance of adrenarche in human physiology remains unknown. In addition, although no DHEA receptor has been genetical y cloned, there are strong data to support the possibility of the existence of a plasma membrane receptor for DHAS (30-31). Adrenarche can be considered as the puberty of the adrenal gland, but the two processes (adrenal and gonadal puberty) are independent. However, androgens of adrenal origin had been postulated to be able to initiate activation of the hypothalamic-pituitary–gonadal axis, because central precocious puberty often occurs in children untreated or poorly treated for congenital adrenal hyperplasia (1,15,32), suggesting a possible relationship between adrenarche and gonadarche.On the contrary, the adrenal insufficiency does not represent a limiting factor for the development of gonadarche (33). Pubarche has often been taken as the clinical sign of adrenarche, therefore, the terms adrenarche and pubarche have been usual y used as synonyms (15,33). However, dissociation between pubarche and biochemical markers of adrenarche can occur in girls with precocious puberty, who have pubarche long before adrenarche (34-35). The NEWBORN ADRENAL GLAND
cell proliferation
Aldosterone
z. glomerulosa
Cortisol
z. fasciculata
fetal zone
adrenal medulla
Epinephrine
FIGURE 1. The newborn adrenal gland stil retains the regressing fetal zone. The medul a has not reach yet an uniforme layer. Cel renewal of al zones takes place in the sub-capsular region. opposite situation has been reported in some girls with Turner syndrome, mainly in those with premature ovarian failure Premature adrenarche, the early increase in adrenal androgen production might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as wel as with insulin resistance in the two sexes, during puberty development, adult life and even in childhood (15,18, 36-42). Then, improving our knowledge on the mechanism involved in the regulation of adrenarche represents an important chal enge for medical science. In this chapter the fol owing topics wil be discussed: 2. Normal adrenarche. Development and zonation of the human adrenal gland. Regulators of adrenal androgen production. The IGF system and insulin sensitivity. 3. Premature adrenarche. ONE-YEAR-OLD ADRENAL GLAND
cell proliferation
Aldosterone
z. glomerulosa
Cortisol
Androstenedione
z. fasciculata
Epinephrine
FIGURE 2. At one year of age the regresión of the fetal zone is complete. 4. Final comments. 2. NORMAL ADRENARCHE
2.1 DEVELOPMENT AND ZONATION OF THE HUMAN ADRENAL GLAND
The developmental program that gives rise to the adrenal gland begins early during embryogenesis and continues into adult life. There are undeniable species-specific dif erences in the structural and functional organization of the human and great primate adrenal cortex compared to non-primate species (43). The fetal adrenal cortex derives from a common adrenogonadal precursor lineage that also gives rise to the steroid-secreting cel s of the gonads. In human embryos, these adrenogonadal progenitors first appear in the fourth week of gestation. Cel s destined to generate the adrenal cortex migrate from the coelomic epithelium forming the primitive adrenal gland by eight weeks of gestation. This rudimentary adrenal gland contains an inner cluster of large, eosinophil cel s, termed the fetal zone. Shortly thereafter, a second group of cel s develops to form a densely packed FOUR-YEAR-OLD ADRENAL GLAND
cell proliferation
Aldosterone
z. glomerulosa
Cortisol
Androstenedione
z. fasciculata
Epinephrine
FIGURE 3. After 2 years of age the adrenal medul a form a continuos layer. outer zone of cel s, the definitive zone. At the same time, the adrenal cortex becomes encapsulated and chromaffin cel s originating from the neural crest migrate through the fetal cortex to progressively colonize the center of the gland to form the future medul a (43-44). However, it is not until 12 to 18 months of age that the medul a becomes adult-like in appearance (45). Genes encoding a number of transcription factors have been linked to adrenocortical cel development and to modulation of steroidogenic function (44,46). The large inner fetal zone expressing cholesterol side-chain cleavage enzyme (CYP11A) and 17α-hydroxylase (CYP17), but not 3β-hydroxysteroid dehydrogenase, is the site of synthesis of large amounts of DHEA and DHEA-S since early in development (47). Definitive zone cel s have a proliferation phenotype that persists throughout gestation, and they acquire mineralocorticoid synthesis capacity only late in POST-ADRENARCHE ADRENAL GLAND
cell proliferation
Aldosterone
z. glomerulosa
Cortisol
Androstenedione
z. fasciculata
z. reticularis
Epinephrine
FIGURE 4. Zona reticularis is completely differentiated and developed. gestation. A third zone, the transitional zone, develops between the definitive and fetal zone around midgestation, and it expresses enzymes required for the synthesis of cortisol (47). After birth, a strong remodeling of the adrenal gland occurs; the medul ary islands coalesce to form a rudimentary medul a, the fetal zone regresses (Figure 1) by the third postnatal month, primarily by apoptosis (3,48), and the definitive zone develops into the adult adrenal. These morphologic changes are accompanied by a rapid drop in DHEA and DHEA-S production due to the involution of the fetal zone. In preadrenarche children, the zona glomerulosa (ZG) and the zona fasciculata (ZF) are clearly present (Figure 2) but only focal islands of ZR cel s, that do not express the enzymes needed to maintain high levels of DHEA-S production, can be identified at age 3 to 5 years of age (Figure 3) (4,19-20,49). After adrenarche, there is a development and thickening of a continuous ZR associated with detectable increases in circulating DHEA and DHEA-S (Figure 4) (4,11,50). Peak levels of DHEA and DHEA-S occur at age 20 to 25 years and decline thereafter (51). This decrease in adrenal androgens with aging is often cal ed adrenopause. There appears to be a reduction in the width of the ZR with aging, without overal changes in the width of the adrenal cortex. This suggests that this phenomenon is specific to the ZR, and not global atrophy of the adrenal gland with aging (51, 52). The origin of the adrenocortical zones and the regulation of their proliferation are incompletely understood. At present there are three theories for the zonation of the adrenal cortex (53). The transformational field theory involves the replacement of zonal tissue by ZF (54-59). The zonal theory involves the equal proliferation of al three zones (55). The third, the progenitor cel proliferation/migration theory, and the most accepted one, proposes that proliferation of cortical cel s takes place in the outermost layers of the adrenal cortex. The theory would be valid for differentiation of ZG and ZF during fetal life, as wel as for ZR during postnatal life. Hence, al cel s of the adrenal cortex would have a common origin, which becomes functional y differentiated in the appropriate zone environment. Although the accumulated data point strongly to the progenitor cel proliferation/migration theory in adrenal gland differentiation, the evidence is not direct. On the other hand, at the other age spectrum of human life, there are few data concerning the mechanisms responsible for the apparent shrinkage of ZR with aging. 2.2 REGULATORS OF ADRENAL ANDROGEN PRODUCTION
The pituitary hormone adrenocorticotrophin (ACTH) is the primary regulator of both fetal adrenal development and adult adrenal cortex homeostasis and steroidogenic function (56, 57-59). Given the variety of biological events triggered by ACTH in the adrenal cortex, it appears that most of these effects are induced by a variety of related proteins synthesized and secreted by the different zones of the cortex, and /or that local y produced factors may synergize or antagonize the direct biological effects of ACTH in order to generate combinatorial responses in the different cel Several experiments and clinical observations have shown that ACTH is necessary but not sufficient to induce adrenarche. Patients with ACTH resistance fail to undergo adrenarche (60, 61), and patient with ACTH deficiency have undetectable DHEA-S levels (62). However, ACTH levels do not change at times when circulating DHEA levels change drastical y, such as during adrenarche or aging (63) suggesting that other factors must be involved in the specific regulation of DHEA and DHEAS synthesis in the adrenal gland. These factors should be involved either in regulation of adrenal enzyme expression and action or in the growth and trophic maintenance of the ZR itself. The roles of several growth factors have been examined. Insulin-like growth factors I and II (IGF-I and IGF-II), acting through type 1 IGF receptor (IGF-R1), affect growth and differentiation of a wide variety of cel types and can act as autocrine, paracrine, or endocrine factors (64). While IGF-I mediates many of the postnatal somatotropic actions of growth hormone (GH), IGF-II has been involved in the regulation of fetal development. Both IGF-I and IGF-II enhance steroidogenic enzyme activity of P450c17 and 3 -HSD (65). In this regard, a recent study of IGF-I, IGF-II and IGF-R1 mRNA expression and immunolocalization in human adrenals from early infancy to late puberty shows a very low IGF-RI expression in the ZR suggesting that the IGF system is not directly involved in the regulation of adrenal androgen via ZR cel s (21). However, it has been proposed that IGF-I and perhaps IGF-II, by autocrine, paracrine or endocrine stimulation, could be a factor involved in the postnatal mechanisms of progenitor adrenal cel proliferation and migration (21). Although IGF-II circulating and tissue levels are highest during fetal life and decrease postnatal y (21, 65) a postnatal role of IGF-II in adrenal gland could not be discarded (21, 66). Basic fibroblast growth factor (bFGF) is a potent mitogen in primary cultures of bovine adult adrenal cortical cel s (67). It also stimulates proliferation of cultured fetal and definitive zone cel s (68). As bFGF is also a potent angiogenic and neurotrophic factor, its trophic effects could be also due to effects on the growth and maintenance of the vascularization and innervation of the adrenal cortex. Nevertheless, little is know about the expression and role of bFGF in postnatal human adrenal gland function, including adrenarche. The possible role of the transforming growth factor 1 (TGF- 1) in adrenarche is not clear. TGF- 1 stimulates 3 - HSD2 activity in adult human adrenal cel s. A local decrease of TGF- 1 production might be involved in the steroid hormone changes observed at adrenarche (69). Interleukin-6 (IL-6) also appears to be a local factor that stimulates DHEA secretion. Interestingly, IL-6 receptor is expressed with high density in the ZR (70). Cytokines produced by the inner zones of the human adrenal cortex, such as tumor necrosis factor (TNF ) (71), would participate in the differentiation and apoptosis of the ZR (72, 73). Recently, an inhibitory effect TNF on the HSD3B2 promoter has been shown, which is in agreement with the low expression of 3 HSD2 in the ZR at adrenarche (74). A potential role for steroids, particularly estradiol, in promoting adrenal androgen production has been suggested. High concentrations of estradiol enhance basal and ACTH stimulated DHEA and DHEA-S production by human fetal adrenal cel s in culture (75, 76). The mechanism of action seems to be a direct inhibition of 3β-HSD2 enzyme activity by high estrogen levels (77). Besides, it has been shown that estradiol increases cel proliferation in the human cel line H295R (78). However, children with gonadal dysgenesis have a normal rise of DHEA-S with chronological age (33). Furthermore, there are no significant sex differences in the age of adrenarche which supports that estrogens are not a major factor. However, estrogen is no solely an endocrine factor, but instead is produced in a number of extragonadal sites and acts local y in a paracrine and intracrine fashion. Within these sites, aromatase action can generate high levels of estradiol local y without significantly affecting circulating levels (79). Taking this into account, it is of interest that a preliminary study described the presence of aromatase expression in prepubertal and pubertal human adrenal glands, as wel as the immunolocalization of estrogen receptor in the ZR (80). More recently, other candidate hormones, related to control of body mass, such as insulin and leptin, have been suggested as the triggers of adrenal growth and adrenarche. In vitro, leptin has been shown to increase the 17, 20 lyase activity of the P450c17 enzyme in human adult adrenal cel s, presumably through P450c17 phosphorylation (81). It is worth mentioning that components of extracel ular matrix can induce intracel ular cel signals or interact with hormonal or growth factor transduction pathways, leading to specific adrenocortical cel behavior, such as proliferation, migration, apoptosis, and gene expression (82-84). Final y, the integrated control of adrenocortical function involves cortico-medul ary interactions, the gland's vascular supply, its neural input, the immune system, growth factors, as wel as signals provided by the extracel ular microenvironment (28, 85). Although the physiological triggers of adrenarche remain speculative, it is reasonable to speculate that adrenarche is probably the result of the interplay of several factors. 2.3 THE IGF SYSTEM AND INSULIN SENSITIVITY
There are some evidences that the GH – IGF system and insulin might be regulating factors of adrenal androgen production at adrenarche. For instance, serum IGF-1 levels rise and fal in a pattern similar to serum DHEAS, and normal puberty is characterized by a state of transient insulin resistance associated with an increase of, not only gonadal sex steroid production, but also adrenal androgens. Thereby, a role has been proposed for the GH - IGF system and insulin on the developmental changes taking place at adrenarche (86-92). As it has been described above, several In vitro studies showed that the IGFsystem and insulin might modulate adrenal steroidogenesis, not only cortisol but also DHEAS secretion. The GH/IGF system and adiposity have been considered the major contributors of insulin resistance at puberty (90, 93-97). Several studies have shown pubertal female-male differences in insulin sensitivity, normal girls being less insulin sensitive than normal boys (90, 96-100). However, we found that these sex differences were clearly evident in late prepuberty, when girls became more insulin-resistant than boys, (98, 100). In addition, a similar finding was described by Hoffman et al (97) in a smal sample of subjects. In vivo studies of the implications of insulin-resistance and the GH/IGF system on the regulation of adrenal androgen secretion, in normal children at adrenarche are scarce. Bloch et al (101) have found that healthy children at adrenarche were more insulin-resistant than younger ones, and an inverse relationship between insulin sensitivity and DHEAS levels were also found .On the contrary, no relationship between DHEAS levels and Insulin sensitivity was observed in normal prepubertal and adolescent subjects of both sexes, by Caprio et al (102). Final y, while Smith et al (103) described a positive correlation between DHEAS levels and basal or stimulated Insulin responses when prepubertal and pubertal children were analysed together, they were unable to detect a significant correlation in the prepubertal group alone. In adult men, in contrast to adult women, DHEAS concentrations correlate positively with insulin sensitivity (104), suggesting a physiological sexual dimorphism. We have studied the relationships between the GH/IGF-1, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys and girls (98, 100). In our study we found that, as previously described (105, 106), serum DHEAS levels increased during prepuberty in both sexes. However, as it is shown in figure 3, and in contrast to Denburg et al. (42), in prepubertal boys, no correlation was found between serum DHEAS levels and insulin sensitivity, or serum DHEAS levels and serum IGF-1 levels, suggesting that neither the GH/IGF-1 axis nor insulin sensitivity are involved in adrenarche. Insulin sensitivity decreased in the transition from early to late puberty in boys fol owing changes in BMI and correlating with DHEAS levels, suggesting that peripheral Insulin could be involved in adrenal androgen steroidogenesis, particularly during early puberty in boys. Contrarily to boys, Guercio et al. found a significant decrease of insulin sensitivity in normal prepubertal girls as wel during pubertad development (100). Although we have not determined serum estradiol in this study, we believe that the sex differences in insulin sensitivity that we have found, might be secondary to differences in the estrogen milieu, since sex steroids, androgens aw wel as estrogens, can regulate insulin sensitivity (107-109) and adipogenesis (110, 111) in opposite ways. In girls, Guercio et al.(100) found a significant negative correlation between serum DHEAS levels and insulin sensitivity during prepubertal and pubertal development, and a positive one between serum DHEAS levels and serum IGF-I, but limited to the prepubertal period. These data suggested that in normal girls insulin is involved in the regulation of adrenal androgen steroidogenesis during the life span and might be one of the peripheral regulators involved in the mechanism of adrenarche in girls. The study of Guercio et al. (100) also suggests that the GH/IGF axis might be an important metabolic signal involved in the maturational changes of human adrenal at the time of Information regarding to serum adrenal androgen levels in growth hormone (GH) deficiency individuals has been conflicting, and limited to a smal number of reports, mainly derived from studies performed in children (112-118). It has been proposed that the presence of an intact ACTH reserve is a necessary feature of the GH–dependent action (119). However, in the few studies available in children, this point was not careful y considered. Although the available data are not conclusive, as it is shown in the scheme in figure 5, we propose that GH might stimulate adrenal androgen production directly or throughout the modification of peripheral or intradrenal IGF system. However, an inhibitory effect of GH on 11beta – HSD type 1(120) activity leading to decreased peripheral cortisol production, and subsequent activation of hypothalamo-pituitary axis has to be ruled out. 3. PREMATURE ADRENARCHE
3.1 DEFINITION. CLINICAL AND LABORATORY CHARACTERISTICS
Premature pubarche is a clinical term used to describe the appearance of pubic hair before the age of 8/9 years in girls/boys, respectively, in the absence of other clinical signs of puberty. Premature or exaggerated adrenarche is defined as the elevation of adrenal androgens above prepubertal levels in children with premature pubarche, provided that the elevation is not due to defined disorders of the gonads or adrenals, such as gonadal precocious puberty, tumors or enzymatic defects of steroidogenesis (121). As published by Guercio et al. (100), in prepubertal girls the normal mean±SD serum dehydroepiandrosterone sulfate level, the main marker of zona reticularis function, was 0.24±0.22 µmol/liter (mean±SD age 5.0±3.08 years). However, there was an age difference during prepuberty. In early prepubertal girls (2.2±1.45 years old), serum dehydroepiandrosterone sulfate was 0.08±0.09 while in late prepuberty (7.5±1.5 years old), values were 0.39±0.22 µmol/liter. The corresponding level in prepubertal boys (169), with a mean±SD age of 5.22±2.29 years, was similar to girls: 0.31±0.33 µmol/liter. An age difference within prepuberty was also found in boys: early prepuberty (3.19±1.0 years old) 0.16±0.20, and late prepuberty (7.13±1.25 years old) 0.46±0.22 µmol/liter. It should be stressed that the increase of serum dehydroepiandrosterone sulfate detected in late prepuberty is the initiation of a long-term biological process of a gradual increment in the serum levels of the steroid, peaking in the early twenties, and fol owed by a slower and gradual decrement during the next decades to reach very low levels at 3.2 DIFFERENTIAL DIAGNOSIS
The differential diagnosis of premature pubarche has important clinical implications. It is more common in girls than in boys (122), and it might be associated with other signs of mild androgen action, such as acné, body hair or advanced bone age. It is mandatory to discard several conditions leading to excessive androgen production. Congenital defects of steroidogenesis are classical y present before birth and, therefore, female external genitalia are masculinized to varying degrees. Mild defects, however, might induce minimal masculinization, and should be discarded. Most commonly, premature pubarche is the first sign of nonclassical 21-hydroxylase deficiency (123). Other congenital defects of steroidogenesis are also possible. Virilizing ovarian or adrenal tumors are extremely rare, but they should be included in the differential diagnosis. One diagnosis to discard is idiopathic precocious puberty. Usual y, this condition starts with breast development (telarche) and, therefore, it is easy to diagnose. However, as it occasional y happens with normal puberty, the onset of pubic hair might precede breast development. Occasional y, medications for CNS disorders might induce the development of premature pubic hair. In boys also, the first condition to differentiate from, is simple virilizing congenital adrenal hyperplasia due to 21- hydroxylase deficiency. These boys do not lose salt, and premature pubarche might be the first sign of androgen excess. Clinical y, there is growth acceleration and increased bone age. The external genitalia are usual y stimulated, contrasting with smal testes, in the first years of life. Later on, chronic androgen excess leads to early maturation of the hypothalamic GnRH pulse generator and development of true precocious puberty. As in girls, virilizing adrenal tumors should be discarded. Testicular disorders are rare. Testicular tumors are usual y palpable, and might be single (usual y Leydig cel tumor) or multiple (Sertoli-Leydig cel tumors). Final y, other conditions, such as familial male precocious puberty produced by gain-of-function mutations of the LH receptor (testotoxicosis), or stimulation of the testes by an hCG-secreting choriocarcinoma should be considered. Imaging studies and laboratory hormonal tests are helpful to establish a correct diagnosis, in the two sexes. Adrenal and ovarian tumors can be detected by appropriate image diagnosis. Since the etiology of idiopathic premature pubarche is unknown, the diagnosis is supported by the detection of a moderate elevation of serum adrenal androgens (usual y dehydroepiandrosterone sulfate), along with the exclusion of the above mentioned disorders. For the detection of 21-hydroxylase deficiency, it is important to determine the basal serum concentration of 17-hydroxyprogesterone along with serum androgens. If they were not elevated, the 17-hydroxyprogesterone response to an iv ACTH test is useful for detecting nonclassical 21-hydroxylase deficiency (124). Final y, analysis of the CYP21 gene wil confirm the 3.3 ASSOCIATION OF PREMATURE ADRENARCHE WITH RISK OF CHRONIC DISEASE AS ADULT
Mounting evidence, arisen in epidemiological studies, indicates that events occurring in the earliest stages of human development, such as fetal growth restriction, may influence the development of several disorders in adulthood, such as central distribution of body fat, insulin resistance, the metabolic syndrome, type 2 diabetes, hypertension and ischemic cardiovascular disease (125). It has been suggested that lower birth weight could result in re-programming a number of metabolic pathways which might have long-term unfavorable consequences on body health. In 1998, Ibañez et al. (40) reported that premature pubarche (and exaggerated adrenarche), hyperinsulinism and ovarian hyperandrogenism were associated with low birth weight, in girls. This finding linked exaggerated adrenarche with the risk of developing central obesity, hyperinsulinism and polycystic ovary syndrome. More recent studies found that the relationship between lower birth weight and higher childhood adrenal androgen levels was similar in boys and girls. Furthermore, adrenal androgen levels were highest in smal for gestational age infants who gained weigh rapidly during childhood (126). Charkaluk et al. (127) studied a large population of children with premature pubarche (n = 216) classified according to their sex and age at onset of pubarche. They confirmed that premature pubarche was rare in boys (13.4 % of the cohort). They suggested that premature pubarche occurring in children aged less than 2 years is probably different from that occurring in older ones. In agreement with previous reports, 4 to 7.9 year old girls with premature pubarche tended to be obese and had a higher incidence of intrauterine growth retardation. Indeed, insulin resistance and hyperinsulinemia are common features seen in prepubertal girls with premature adrenarche. In many of these girls, significantly high ACTH-stimulated ∆5-steroid levels (17hydroxypregnenolone and DHEA), associated with low SHBG, low IGFBP-1, high IGF-1 levels and an altered lipid profile have been reported. It has been shown that ACTH-stimulated hormones correlated inversely with insulin sensitivity and directly with IGF-1 levels, suggesting that hyperandrogenism might be linked to Insulin resistance and the IGF system (36-39,128-130). Administration of metformin to girls with premature pubarche appears to prevent the increase in DHEAS levels (131). Obesity was more frequently reported in girls with precocious pubarche and the correlations between DHEAS levels and adiposity indexes suggests that overweight might influences the onset of adrenarche (38, 39, 130-133). Moreover, in normal children, a greater increase in urinary DHEAS during the period of the greatest rise in BMI was found (134). These effects might be related to an increased of insulin and leptin levels, associated with an increased adiposity (134, 135). Leptin has been implicated in adrenarche by modulating CYP17 phosphorylation (81). However, in girls with precocious adrenarche, serum leptin levels have been found to be similar (136) or higher (132) than in On the other hand, the GH-IGF-1 system might modulate adrenal androgens (137). Indeed, a report by Silfen et al. (39) found that insulin levels in hispanic girls with premature adrenarche did not differ from that of control girls, but IGF-1 was higher and IGFBP-1 lower in premature adrenarche. It is then evident that premature adrenarche shares many characteristics with PCOS, suggesting that they might be different expression of similar underlying disorders. Therefore, the risk of developing PCOS at adolescence or soon thereafter in girls with premature adrenarche should alert primary care physicians to fol ow the evolution of sexual development, age of menarche and menstrual cycles in these girls. On the basis of the evidence discussed above, premature pubarche has to be included among conditions prone to develop central obesity, insulin resistance and its complications for adult life. It is advisable, then, in clinical practice to study these children in terms of body mass index, insulin sensitivity and lipid profile to assess the feasibility of implementing preventing measures involving quality and quantity of food intake, recreational activities and exercise. 4. FINAL COMMENTS
The mechanism behind precocious adrenarche is as intriguing as that behind normal adrenarche. From a cel ular perspective, adrenarche depends on the mechanisms regulating post natal zonation of ZR. As stated above, the migration theory of zonal formation assumes that, starting at the age of 6 years, proliferation of progenitor cel s would take place in the periphery of the cortex, fol owed by migration of these cel s toward the center of the gland. Upon arrival, these cel s would place themselves adjacent to focal areas of ZR cel s, already present, and they would acquire expression of genes specific for ZR cel s. This process of cel accumulation would result in the formation of a new zone. In premature pubarche, ZR formation would start earlier and/or it is exaggerated. The trigger for this earlier activation of ZR differentiation could act at the level of progenitor cel proliferation, migration, cel differentiation or, perhaps, at It is interesting that adrenarche requires the permissive presence of basal levels of ACTH, but that ACTH is not the primary stimulator. On the other hand, under an acute iv ACTH stimulation (post adrenarche) there is no response of serum DHEAS during the first hours, but there is a response after several days, suggesting that the response might need proliferation of ZR cel s. Activation of IGF-1 R by high levels of insulin in patients with insulin resistance, or by IGF- 1 in other subjects (39), might induce proliferation of adrenal progenitor cel s in some girls with premature or exaggerated adrenarche. Estrogens might participate in the mechanism of premature adrenarche at the level of ZR cel differentiation through activation of ER . To explain the higher incidence of premature pubarche in girls compared to boys, it might be proposed that peripheral estrogens could be added to local estrogens synthesized by adrenal medul a aromatase, to act on ER (80). Furthermore, DHEA itself, but not DHEAS, can be an agonistic ligand for ER (137), suggesting the existence of a positive feedback system within ZR. Other potential candidate factors playing a role in normal differentiation of ZR cel s, such as cytokines (IL-6, TNF ), leptin, components of the extracel ular matrix or of adrenal medul a, might be responsible of premature adrenarche. Until recently, the secretion of adrenal androgens, as wel as the growth of pubic hair in children, was considered as a trivial physiological event, and premature pubarche a minor deviation of normality. However, the numerous recent studies discussed in this review have changed our concept of these events. However, many questions remain with incomplete answers, such as, 1) the mechanisms of adrenarche and premature adrenarche, 2) the physiological actions of adrenal androgens, acting as either direct ligands or pro-hormones, and 3) the relationship between activation of adrenal androgen secretion, growth restriction during fetal life and chronic diseases in adulthood, transforming adrenal androgens in markers of diseases important for human health. Future research might contribute to provide responses for a better understanding of these questions. REFERENCES
Parker LN. Adrenarche. Endocrinol Metab Clin North Am 1991;20:71-83. Kennerson AR, McDonald DA, Adams JB. Dehydroepiandrosterone sulfotransferase localization in human adrenal glands: a light and electron microscopic study. J Clin Endocrinol Metab 1983;56:786-790. Bech K, Tygstrup I, Nerup J. The involution of the foetal adrenal cortex. A light microscopic study. Acta Pathol Microbiol Scand 1969;76:391-400. Dhom G. The prepuberal and puberal growth of the adrenal (adrenarche). Beitr Pathol 1973;150:357-377. Grumbach MM, Richards HE, Conte FA, Kaplan SL. Clinical Disorders of adrenal function and puberty: assessment of the role of the adrenal cortex and abnormal puberty in man and evidence for an ACTH-like pituitary adrenal androgen stimulating hormone. In: James VHT, Giusti G, Martini L, eds. The Endocrine Function of the Human Adrenal Cortex, vol. 18. New York: Academic Press, 1978:583-612. Urban MD, Lee PA, Gutai JP, Migeon CJ. Androgens in pubertal males with Addison's disease. J Clin Endocrinol Metab 1980;51:925-929. Forest ME, Saez JM, Bertrand J Present concept of initiation of puberty— neonatal and prepubertal hormonal influences. In: Franchimont P (ed) Some Aspects of Hypothalamic Regulation of Endocrine Functions. Schattauer Verlag, Stuttgart, 1975:339–366. Korth-Schutz S, Levine LS, New MI. Serum androgens in normal prepubertal and pubertal children with precocious adrenarche. J Clin Endocrinol Metab 1976;42:117–124. Korth-Schutz S, Levine LS, New MI. Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion. J Clin Endocrinol Metab 1976;42:1005–1013. 10. Hopper BR, Yen SCC. Circulating concentrations of dehydro-epiandrosterone and dehydroepiandrosterone sulfate during puberty. J Clin Endocrinol Metab 1975;40:458–461. 11. dePeretti E, Forest MG. Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in humans: the use of a sensitive radioimmunoassay. J Clin Endocrinol Metab 1976;43:982–991. 12. Reiter E, Fuldauer VG, Root AW. Secretion of the adrenal androgen, dehydroepiandrosterone sulfate during normal infancy, childhood and adolescence, in sick infants and in children with endocrinologic abnormalities. J Pediatr 1977;90:766–770. 13. Forest MG. Age-related response to plasma testosterone, 4- androstenedione, and cortisol to adrenocorticopin in infants, children and adults. J Clin Endocrinol Metab 1978;47:931–937. 14. dePeretti E, Forest MG. Pattern of plasma dehydroepiandrosterone sulfate levels in humans from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab 1978; 47:572–577. 15. Ibáñez L, DiMartino –Nardi J, Potau N, Saenger P. Premature adrenarche—Normal variant or forerunner of adult disease? Endocr Rev 2000;21:671-696. 16. Remer T, Boye KR, Hartmann MF, Wudy SA. Urinary markers of adrenarche: Reference values in healthy subjects, aged 3–18 years. J Clin Endocrinol Metab 2005;90:2015-2021. 17. Albertson BD, Hobson WC, Burnett BS, Turner PT, Clark RV, Schiebinger RJ, Loriaux DL, Cutler GB Jr. Dissociation of cortisol and adrenal androgen secretion in the hypophysectomized, adrenocorticotropin-replaced chimpanzee. J Clin Endocrinol Metab. 1984;59:13-18. 18. Zhang L, Rodríguez H, Ohno S, Miller WL Serine phosphorylation of human P450c17 increases 17,20 lyase activity: implications for adrenarche and for the polycystic ovary syndrome. Proc Natl Acad Sci USA 1995;92:10619-10623. 19. Gell JS, Carr BR, Sasano H, Atkins B, Margraf L, Mason JI, Rainey WE Adrenarche results from development of a 3β-hydroxysteroid dehydrogenase-deficient adrenal reticularis. J Clin Endocrinol Metab 1998;83:3695-3701. 20. Dardis A, Saraco N, Rivarola MA, Belgorosky A. Decrease in the expression of the 3β-hydroxysteroid dehydrogenase gene in human adrenal tissue during prepuberty and early puberty. Implications to the mechanism of adrenarche. Pediatr Res 1999;45;384-388. 21. Baquedano MS, Berensztein E, Saraco N, Dorn GV, Davila MTG de, Rivarola MA, Belgorosky A. Expression of IGF system in human adrenal tissues from early infancy to late puberty. Implications for the development of adrenarche. Pediatr Res 2005;58:451-458. 22. Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev 1988; 9:295-318. 23. John ME, John MC, Boggaram V, Simpson ER, Waterman MR. Transcriptional regulation of steroid hydroxylase genes by corticotrophin. Proc Natl Acad Sci USA 1986;83:4715-4719. 24. Miller WL, Auchus RJ, Geller DH. The regulation of 17,20 lyase activity. Steriods 1997;64:133-142. 25. Auchus RJ, Lee TC, Miller WL. Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron tranfer. J Biol Chem 1998;273:3158-3165. 26. Dharia S, Slane A, Jian M, Conner M, Conley AJ, Parker CR Jr. Colocalization of P450c17 and cytochrome b5 in androgen-synthesizing tissues of the human. Biol Reprod 2004;71:83-88. 27. Pandey AV, Mellon SH, Miller WL. Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. J Biol Chem 2003;278: 2837-2844. 28. Ehrhart-Bornstein M, Hinson JP, Bornstein SR, Scherbaum WA, Vinson GP. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998;19:101-143. 29. Siiteri PK, MacDonald PC. Placental estrogen biosynthesis during human pregnancy. J Clin Endocrinol Metab 1966;26:751-761. 30. Ohno T, Imai A, Tamaya T. Possible evidence that dehydroepiandrosterone sulfate (DHA-S) stimulates cervical ripening by a membrane-mediated process: specific binding-sites in plasma membrane from human uterine cervix. Res Commun Chem Pathol Pharmacol 1991;72:117-120. 31. Imai A, Ohno T, Tamaya T. Dehydroepiandrosterone sulfate binding- sites in plasma membrane from human uterine cervical fibroblasts. Experientia 1992;48:999-1002. 32. Belgorosky A, Rivarola MA. Irreversible increase of serum IGF-1 and IGFBP-3 levels in central precocious puberty of different etiologies. Implications for the onset of puberty. Horm Res 1998;49:226-32. 33. Sklar CA, Kaplan SL, Grumbach MM. Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence. J Clin Endocrinol Metab 1980;51:548–556 34. Wierman ME, Beardsworth DE, Crawford JD, Crigler Jr JF, Mansfield MJ, Bode HH, Boepple PA, Kushner DC, Crowley Jr WF. Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche. J Clin Invest 1986;77:121–126. 35. Martin D, Schweizer R, Philipp Schwarze C, Elmlinger M, Ranke M, Binder G. The early dehydroepiandrosterone sulfate rise of adrenarche and the delay of pubarche indicate primary ovarian failure in Turner syndrome. J Clin Endocrinol Metab 2004;89:1164-1168. 36. Ibañez L, Potau N, Zampolli, Riquè S, Saenger P, Carrascosa A. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature adrenarche. J Clin Endocrinol Metab 1997;82: 2283-2288. 37. Banerjee S, Raghavan S, Wasserman EJ, Linder BL, Saenger P, DiMartino-Nardi J. Hormonal findings in african-american and caribbean hispanic girls with premature adrenarche: implications for polycystic ovarian syndrome. Pediatrics 1998;102:E36. 38. Vuguin P, Linder B, Rosenfeld RG, Saenger P, DiMartino-Nardi J. The role of insulin sensitivity, insulin-like growth factor and insulin-like growth factor binding proteins 1 y 3 in the hyperandrogenism of african-american and caribbean hispanic girls with premature adrenarche. J Clin Endocrinol Metab 1999;84:2037-2042. 39. Silfen ME, Manibo AM, Ferin M, McMahon DJ, Levine LS, Oberfield SE. Elevated free IGF-1 levels in prepubertal hispanic girls with premature adrenarche: relationship with hyperandrogenism and insulin sensitivity. J Clin Endocrinol Metab 2002;87:398-403. 40. Ibañez L, Potau N, Francois I, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogensim in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 1998;83:3558-3562. 41. Potau N, Ibañez L, Rique S, Sanchez-Ufarte C, de Zegher F. Pronounced adrenarche and precocious pubarche in boys. Horm Res 1999;51:238-241. 42. Denburg MR, Silfen ME, Manibo AM, Chin D, Levine LS, Ferin M, McMahon KJ, Go Christina, Oberfield SE. Insulin sensitivity and the insulin-like growth factor system in prepubertal boys with premature adrenarche. J Clin Endocrinol Metab 2002;87:5604-5609. 43. Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 1997;18:378-403. 44. Keegan CE, Hammer GD. Recent insights into organogenesis of the adrenal cortex. Trends Endocrinol Metab 2002;13:200-208. 45. Bocian-Sobkowska J, Wosniak W, Malendowicz L. Stereology of human fetal adrenal medulla. Histol Histopathol 1996;11: 389-393. 46. Hammer GD, Parker KL, Schimmer BP Minireview: Transcriptional regulation of adrenocortical development. Endocrinol 2005;146:1018-1024. 47. Mesiano S, Coulter CL, Jaffe RB. Localization of cytochrome P450 cholesterol side chain cleavage, cytochrome p450/17,20 lyase and 3β-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation. J Clin Endocrinol Metab 1993;77:1184-1189. 48. Spencer SJ, Mesiano S, Lee JY, Jaffe RB. Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling. J Clin Endocrinol Metab 1999;84:1110-1115. 49. Suzuki T, Sasano H, Takeyama J, Kaneko C, Freije W, Carr R, Rainey WE. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol (Oxf) 2000;53:739-747. 50. Endoh A, Kristiansen SB, Casson PR, Buster JE, Hornsby PJ. The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3β-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 1996; 81:3558-3565. 51. Migeon CJ, Keller AR, Laurence B, Shepard THI. Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex, day to day and diurnal variations. J Clin Endocrinol Metab 1957;17:1051-1056. 52. Parker CR Jr, Mixon RL, Brissie RM, Grizzle WE. Aging alters zonation in the adrenal cortex of men. J Clin Endocrinol Metab 1997;82:3898-3901. 53. Wolkersdorfer G, Bornstein SR. Tissue remodeling in the adrenal gland. Biochem Pharmacol 1998;56:163-171. 54. Thomas M, Northrup SR, Hornsby PJ. Adrenocortical tissue formed by transplantation of normal clones of bovine adrenocortical cells in scid mice. Nature Med 1997;3:978-983. 55. Sarason EL. Morphological changes in the rat's adrenal cortex under various experimental conditions. Arch Pathol 1997;35:373-390. 56. Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996;17:221-244. 57. Allen RG, Carey C, Parker JD, Mortrud MT, Mellon SH, Low MJ. Targeted ablation of pituitary pre-pro-opiomelanocortin (POMC) cells by herpes simplex viru-1 thymidine kinase differentially regulates messenger RNAs encoding the ACTH receptor, and aldosterone synthase in the mouse adrenal gland. Mol Endocrinol 1995;9:1005-1016. 58. Simpson ER, Waterman MR. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol 1988;50:427-440. 59. Clark BJ, Soo SC, Caron KM, Ikeda, Y, Parker KL, Stocco DM. Hormonal and developmental regulation of the steroidogenic acute regulatory protein. Mol Endocrinol 1995;9:1346-1355. 60. Ishii T, Ogata T, Sasaki G, Sato S, Kinoshita EI, Matsuo N. Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH. Clin Endocrinol (Oxf) 2000;53:289-392. 61. Weber A, Clark AJ, Perry LA, Honour JW, Savage MO. Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche. Clin Endocrinol (Oxf) 1997;46:431-437. 62. Murch SH, Carter EP, Tsagarakis S, Grossman A, Savage MO. Isolated ACTH deficiency with absent response to corticotrophin-releasing factor-41. Evidence for a primary pituitary defect. Acta Pediatr Scand 1991;80:259-261. 63. Apter D, Pakkerinen A, Hammond GI, Vihko R. Adrenocortical function and puberty, serum ACTH cortisol and dehydroepiandrosterone in girls and boys. Acta Pediatr Scand 1979;69:599-606. 64. Daughday WH, Rotwein P. Insulin-like growth factors I and II: Peptide, messenger ribonucleic acid and gene structure, serum and tissue concentrations. Endocr Rev 1989;10:68-91. 65. L'Al emand D, Penhoat A, Lebrethon MC, Ardevol R, Baehr V, Oelkers W, Saez JM. Insulin Like Growth factors enhance steroidogenic enzyme and corticotrophin receptor messenger ribonucleic acid levels and corticotrophin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 1996;81:3892-3897. 66. Wolf E, Kramer R, Blum WF, Foll J, Brem G. Consequences of postnatally elevated insulin-like growth factor-II in transgenic mice: endocrine changes and effects on body and organ growth. Endocrinol 1994;135:1877-1886. 67. Schweigerer L, Neufeld G, Friedman J, Abraham JA,Fiddes JC, Gospodarowicz D. Basic fibroblast growth factor: production and growth stimulation in cultured adrenal cortex cells. Endocrinol 1987;120:796-800. 68. Mesiano S, Mellon SH, Gospodarowicz D, Di Blasio AM, Jaffe RB. Basic fibroblast growth factor expression is regulated by ACTH in the human fetal adrenal: a model for adrenal growth regulation. Proc Natl Acad Sci USA 1991; 88:5428-5431. 69. Lebrethon MC, Jaillard C, Navil e D, Begeot M, Saez JM. Effects of transforming growth factor-beta 1 on human adrenocortical fasciculata-reticularis cell differentiated functions. J Clin Endocrinol Metab 1994;79:1033-1039. 70. Päth G, Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis. J Clin Endocrinol Metab 1997;82:2343-2349. 71. Gonzalez- Hernandez JA, Ehrhart-Bornstein M, Späth-Schwalbe E, Scherbaum WA, Bornstein SR. Human adrenal cells express TNF -mRNA: evidence for a paracrine control of adrenal function J Clin Endocrinol Metab 1996;81:807-813. 72. Marx C, Bornstein SR, Wolkersdörfer GW, Peter M, Sippel WG, Scherbaum WA. Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex. J Clin Endocrinol Metab 1997;82:3136-3140. 73. Wolkersdörfer GW, Ehrhart-Bornstein M, Brauer S, Marx C, Scherbaum WA, Bornstein SR. Differential regulation of apoptosis in the normal human adrenal gland. J Clin Endocrinol Metab 1996;81:4129-4136. 74. Saraco N, Pepe C, Berensztein E, Rivarola MA, Belgorosky A. Estradiol and TNF interaction on 3 -Hidroxiesteroid dehydrogenase type 2 (3 HSDII) promoter regulation. Horm Res 2005;64 (Suppl 1) Abstract #OR14-139. 75. Fujieda K, Faiman C, Feyes Fi, Winter JSD. The control of steroidogenesis by human fetal adrenal cells in tissue cultures, IV, The effects of exposure to placental steroids. J Clin Endocrinol Metab 1982;54:89-94. 76. Mesiano S, Jaffe RB. Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal towards dehydroepiandrosterone sulfate production. J Clin Endocrinol Metab 1993;77: 754-758. 77. Gell JS, Oh J, Rainey E, Carr BR. Effect of estradiol on DHEAS production in the human adrenocortical cell line, H295R. J Soc Gynecol Invest 1998;5:144-148. 78. Montanaro D, Maggiolini M, Recchia AG, Sirianni R, Aquila S, Barzon L Fallo F, Andò S, Pezzi V. Antiestrogens upregulate estrogen receptor expression and inhibit adrenocortical H295R cel proliferation. J Mol Endocrinol 2005;35:245-256. 79. Simpson E, Rubin G, Clyne C, Robertson K, O'Donnell L, Jones M, Davis S. The role of local estrogen biosynthesis in males and females. Trends Endocrinol Metab 2000;11:184-188. 80. Baquedano MS, Saraco N, Berensztein E, Davila MTG de, Rivarola M, Belgorosky A. Expression of the IGF system, aromatase, ER and ER in human adrenal tissue as a function of age. Implications for adrenarche. Proccedings of 2005 Endocrine Society Annual Meeting; June 4, 2005, San Diego, CA; Abstract #P1-133. 81. Biason-Lauber, A Zachmann M, Schoenle EJ. Effect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche. Endocrinol 2000;141:1446-1454. 82. Adams JC, Watt FM. Regulation of development and differentiation by the extracellular matrix. Development 1993;117:1183-1198. 83. Boudreau N,Bissel MJ. Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr Opin Cell Biol 1998;10:640-646. 84. Chamoux E, Narcy A, Lehoux JG, Gallo Payet N. Fibronectin, Laminin and collagen IV as modulators of cell behavior during adrenal gland development in the human fetus. J Clin Endocrinol Metab 2002;87:1819-1828. 85. Chamoux E. A connection between extracellular matrix and hormonal signals during the development of the human fetal adrenal gland. Braz J Med Biol Res 2005;38:1495-1503. 86. Amiel S, Sherwin R, Simonson D, Lauritano A, Tamborlane W. Impaired insulin action in puberty-A contributing factor to poor glycemic control in adolescents with diabetes. N Engl J Med 1986;315:215-219. 87. Biason-Lauber A, Kempken B, Werder E, Forest MG, Einaudi S, Ranke M, Matsuo N, Brunelli V, Schönle E, Zachmann M. 17α-Hydroxilase/17,20-lyase Deficiency as a model to study enzymatic activity regulation: role of phosphorylation. J Clin Endocrinol Metab 2000;85:1226-1231. 88. Amiel SA, Caprio S, Sherwin RS, Plewe G, Haymond MW, Tamborlane WV. Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism J Clin Endocrinol Metab 1991;72:277-282. 89. Hindmarsh P, Di Silvio L, Pringle PJ, Kurtz AB, Brook CGD. Changes in serum insulin concentration during puberty and their relationship to growth hormone. Clin Endocrinol (Oxf) 1988;21:381-388. 90. Travers SH, Labarta JI, Gargosky SE, Rosenfeld RG, Jeffers BW, Eckel RH. Insulin-like growth factor binding protein-I levels are strongly associated with insulin sensitivity and obesity in early pubertal children. J Clin Endocrinol Metab 1998;83:1935-1939. 91. lofqvist C, Andersson E, Gelander L, Rosberg S, Blum W, Wikland KA. Reference values for IGF-1 throughout childhood and adolescence: a model that accounts simultaneously for the effect of gender, age and puberty. J Clin Endocrinol Metab 2001;86:5870-5876. 92. Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebae NS. Serum Insulin-like growth factor-1 en 1030 healthy children, adolescents and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 1994;78:744-752. 93. Clemmons DR. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. J Clin Invest 2004;113:25-27. 94. Caprio S. Insulin the other anabolic hormone of puberty. Acta Pædiatr Suppl 1999;433:84-7. 95. Moran A, Jacobs DR, Steinberger J, Cohen P, Hong C-P, Prineas R, Sinaiko SR. Association between the insulin resistance of puberty and the insulin-like growth factor-1/growth hormone axis. J Clin Endocrinol Metab 2002;87:4817-4820. 96. Travers SH, Jeffers BW, Bloch CA, Hill JO, Eckel RH. Gender and Tanner stage differences in body composition and insulin sensitivity in early pubertal children. J Clin Endocrinol Metab 1995;80:172-178. 97. Hoffman RP, Vicini P, Sivitz WI, Cobel i C. Pubertal adolescent male-female differences in insulin sensitivity and glucose effectiveness determined by the one compartment minimal model. Pediat Res 2000; 48:384-388. 98. Guercio G, Rivarola MA, Chaler E, Maceiras M, Belgorosky A. Relationship between the GH/IGF-1, Insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys. J Clin Endocrinol Metab 2002; 87:1162-1169. 99. Arslanian SA, Heil BV, Becker DJ, Drash AL. Sexual dimorphism in insulin sensitivity in adolescents with insulin dependent diabetes mellitus. J Clin Endocrinol Metab 1991;72:920-926. 100. Guercio G, Rivarola MA, Chaler E, Maceiras M, Belgorosky A. Relationship between the the GH/IGF-1, Insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls. J Clin Endocrinol Metab 2003;88:1389-1393. 101. Bloch CA, Clemons P, Sperling MA. Puberty decreases insulin sensitivity. J Pediatr 1987;110,481-487. 102. Caprio S, Plewe G, Diamond MP, Simonson DC, Boulware SD, Sherwin RS,Tamborlane WV. Increased insulin secretion in puberty: a compensatory response to reduction in insulin sensitivity. J Pediatr 1989;114:963-967. 103. Smith CP, Dunger DB, Williams AJK, Taylor AM, Perry LA, Gale EAM, Preece MA, Savage MO. Relationship between insulin, insulin-like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life. J Clin Endocrinol Metab. 1989;68:932-937. 104. Nestler JE, Beer NA, Jakubowicz DJ, Beer RM. Effects of a reduction in circulating insulin by Metformin on serum dehydroepiandrosterone sulfate in nondiabetic men. J Clin Endocrinol Metab 1994;78:549-554. 105. Forest MG. Physiological changes in circulating androgens. In: Forest MG, ed. Androgens in Childhood, Pediatr Adolesc Endocrinol. Basel: Karge, 1989:104-129. 106. Belgorosky A, Rivarola MA. Progressive increase in non-sex hormone-binding globulin-bound testosterone and estradiol from infancy to late prepuberty in girls. J Clin Endocrinol Metab 1988;67:234-237. 107. Singh AB, Hsia S, Alaupovic P, Sinha-Hikim I, Woodhouse L, Buchanan TA, Shen R, Bross R, Berman N, Bhasin S. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin Endocrinol Metab 2002;87:136-143. 108. Lind T. Metabolic changes in pregnancy relevant to diabetes mellitus. Postgrad Med 1979;55:353-357. 109. Hollingsworth DR. Alterations of maternal metabolism in normal and diabetic pregnancies: difference in insulin-dependent, non insulin- dependent and gestational diabetes. Am J Obstet Gynecol 1983;146:417-429. 110. Collison M, Campbell IW, Salt IP, Dominiczak AF, Connell JM, Lyall H, Gould GW. Sex hormones induce insulin resistance in 3T3-L1 adipocytes by reducing cellular content of IRS proteins. Diabetol 2000;43:1374-1380. 111. Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: Evidence for sex and site-related specificities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor γ2. Endocrinol 2000;141:649-656. 112. Cohen HN, Wallace AM, Beatsall GH, Fogelman I, Thompson JA. Clinical value of adrenal androgen measurement in the diagnosis of delayed puberty. Lancet 1981;1:689-692. 113. Ilondo MM, Vanderschueren-Lodeweyckx M, Vlietinck R, Pizarro M, Malvaux P, Eggermont E, Eeckels R. Plasma androgens in children and adolescents. Part II. A longitudinal study in patients with hypopituitarism. Horm Res 1982;16:78-95. 114. Lew LQ, Sklar CA, Yoon DJ, David R. Adrenal androgens in children with short stature. Horm Res 1988;29:151-155. 115. Juul A, Andersson AM, Pedersen SA, Jorgensen JO, Christiansen JS, Groome NP, Skakkebaek NE. Effects of growth hormone replacement therapy on IGF-related parameters and on the pituitary-gonadal axis in GH-deficient males. A double-blind, placebo-controlled crossover study. Horm Res 1998;49:269-278. 116. Leschek EW, Troendle JF, Yanovski JA, Rose SR, Bernstein DB, Cutler GB Jr, Baron J. Effect of growth hormone treatment on testicular function, puberty, and adrenarche in boys with non-growth hormone-deficient short stature: a randomized, double-blind, placebo-controlled trial. J Pediatr 2001;138:406-410. 117. Sklar CA, Ulstrom RA. Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency. Hormone Research 1984;20:166-171. 118. Rudd BT, Rayner PH, Basset RM, Williams JW. Serum dehydroepiandrosterne (DHA) and sulphate (DHEAS) after acute growth hormone therapy. Acta Paediatrica Scandinava 1980;69:287-292. 119. Isidori AM, Kaltsas GA, Perry L, JM Burrin, Besser GM, Monson JO. The effect of growth hormone replacement therapy on adrenal androgen secretion in adult onset hypopituitarism. Clin Endrocrinol (Oxf) 2003;58:601-611. 120. Moore JS, Monson JP, Kaltsas G, Putignano P, Wood PJ, Sheppard MC, Besser GM, Taylor NF, Stewart PM. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies. J Clin Endocrinol Metab 1999;84:4172-4177. 121. Sopher AB, Thornton JC, Silfen ME, Manibo A, Oberfield SE, Wang J, Pierson RN Jr, Levine LS, Horlick M. Prepubertal Girls with Premature Adrenarche Have Greater Bone Mineral Content and Density Than Controls. The J Clin Endocrinol Metab 2001; 86: 5269-5272 122. Lee PA. Disorders of Puberty. In: Lifshitz F, ed. Pediatric Endocrinology, 3rd Edition, Marcel Decker Inc, New York, 1996. 123. Dacou-Voutetakis C, M. Dracopoulou M. High Incidence of Molecular Defects of the CYP21 Gene in Patients with Premature Adrenarche. J Clin Endocrinol Metab 1999; 84:1570-1574 124. New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, Dupont B, Stoner E, Levy DJ, Pang S, Levine LS. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data.J Clin Endocrinol Metab 1983;57:320-326. 125. Gillman MW. Developmental origins of health and disease. N Engl J Med 2005;353:1848-1850. 126. Ong KK, Potau N, Petry CJ, Jones R, Ness AR, Honour JW, de Zegher F, Ibáñez L, Dunger DB, Avon Longitudinal Study of Parents Children (ALSPAC) Study Team. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. J Clin Endocrinol Metab 2004;89: 2647-2651. 127. Charkaluk M-L, Trivin C, Brauner R. Premature pubarche as an indicator of how body weight influences the onset of adrenarche. Eur J Pediatr 2004;163:89-93. 128. Ibañez L, Potau N, Chacon P, Pascual C, Carrascosa A. Hyperinsulinemia, dyslipidemia and cardiovascular risk in girls with a history of premature pubarche. Diabetol 1998;41:1057-1063. 129. Vuguin P, Saenger P, Dimartino-Nardi J. Fasting glucose Insulin ratio: a useful measure of insulin resistance in girls with premature adrenarche. J Clin Endocrinol Metab 2001;86:4618-4621. 130. Guven A, Cinaz P, Ayvali E. Are growth factors and leptin involved in the pathogenesis of premature adrenarche in girls? J Pediatr Endocrinol Metab 2005;18:785-791. 131. Ibañez l, Valls C, Marcos MV, Ong K, Dunger DB, De Zegher F. Insulin sensitization for girls with precocious pubarche and with risk for polycystic ovary syndrome: effects of prepubertal initiation and pospubertal discontinuation of metformin treatment. J Clin Endocrinol Metab 2004;89:4331-4337. 132. Cizza G, Dorn L, Lotsikas A, Rotenstein D, Chrousos G. Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study. Horm Metab Res 2001; 33:138-143. 133. Ibañez L, Ong K, de Zegher F, Marcos MV, del Rio L, Dunger DB. Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche. Clin Endocr 2003;58:372-379. 134. Remer T, Manz F. Role of nutritional status in the regulation of adrenarche. J Clin Endocrinol Metab 1999; 84:3396-3944. 135. Simone MD, Farello G, Palumbo M, Gentile T, Ciuffreda M, Olioso P, Cinque M, Matteis FD. Growth charts, growth velocity and bone development in childhood obesity. Int J Obes Relat Metab Disord 1995;19:851-857. 136. L'Al emand D, Schmidt S, Rousson V, Brabant G, Gasser T, Grüters A. Associations between body mass, leptin, IGF-1 and circulating adrenal androgens in children with obesity and premature adrenarche. Eur J Endocrinol 2002;146 :537-543. 137. Chen F, Knecht K, Birzin E, Fisher J, Wilkinson H, Mojena M, Tudela Moreno C, Schmidt A, Harada S, Freedman LP, Reszka AA. Direct Agonist/Antagonist Functions of Dehydroepiandrosterone. Endocrinol 2005;146:4568 - 4576.

Source: http://www.endopedonline.com.ar/img/Numero%209/Review%20Adrenarche.pdf