The Search for the Causes of Common Hyperandrogenism, 1965 to Circa 2015.

From 1965 to 2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, androgen secretion, obesity, phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large-scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

Normal and Premature Adrenarche.

Adrenarche is the maturational increase in adrenal androgen production that normally begins in early childhood. It results from changes in the secretory response to adrenocorticotropin (ACTH) that are best indexed by dehydroepiandrosterone sulfate (DHEAS) rise. These changes are related to the development of the zona reticularis (ZR) and its unique gene/enzyme expression pattern of low 3ß-hydroxysteroid dehydrogenase type 2 with high cytochrome b5A, sulfotransferase 2A1, and 17ß-hydroxysteroid dehydrogenase type 5. Recently 11-ketotestosterone was identified as an important bioactive adrenarchal androgen. Birth weight, body growth, obesity, and prolactin are related to ZR development. Adrenarchal androgens normally contribute to the onset of sexual pubic hair (pubarche) and sebaceous and apocrine gland development. Premature adrenarche causes ≥90% of premature pubarche (PP). Its cause is unknown. Affected children have a significantly increased growth rate with proportionate bone age advancement that typically does not compromise growth potential. Serum DHEAS and testosterone levels increase to levels normal for early female puberty. It is associated with mildly increased risks for obesity, insulin resistance, and possibly mood disorder and polycystic ovary syndrome. Between 5% and 10% of PP is due to virilizing disorders, which are usually characterized by more rapid advancement of pubarche and compromise of adult height potential than premature adrenarche. Most cases are due to nonclassic congenital adrenal hyperplasia. Algorithms are presented for the differential diagnosis of PP. This review highlights recent advances in molecular genetic and developmental biologic understanding of ZR development and insights into adrenarche emanating from mass spectrometric steroid assays.

Approach to the Virilizing Girl at Puberty.

Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows signs of prenatal male hormone exposure at birth. In girls, androgen levels are low during pregnancy and childhood. A first physiologic rise of adrenal androgens is observed at the age of 6 to 8 years and reflects functional activation of the zona reticularis of the adrenal cortex at adrenarche, manifesting clinically with first pubic and axillary hairs. Early adrenarche is known as "premature adrenarche." It is mostly idiopathic and of uncertain pathologic relevance but requires the exclusion of other causes of androgen excess (eg, nonclassic congenital adrenal hyperplasia) that might exacerbate clinically into virilization. The second modest physiologic increase of circulating androgens occurs then during pubertal development, which reflects the activation of ovarian steroidogenesis contributing to the peripheral androgen pool. However, at puberty initiation (and beyond), ovarian steroidogenesis is normally devoted to estrogen production for the development of secondary female bodily characteristics (eg, breast development). Serum total testosterone in a young adult woman is therefore about 10- to 20-fold lower than in a young man, whereas midcycle estradiol is about 10- to 20-fold higher. But if androgen production starts too early, progresses rapidly, and in marked excess (usually more than 3 to 5 times above normal), females will manifest with signs of virilization such as masculine habitus, deepening of the voice, severe acne, excessive facial and (male typical) body hair, clitoromegaly, and increased muscle development. Several medical conditions may cause virilization in girls and women, including androgen-producing tumors of the ovaries or adrenal cortex, (non)classical congenital adrenal hyperplasia and, more rarely, other disorders (also referred to as differences) of sex development (DSD). The purpose of this article is to describe the clinical approach to the girl with virilization at puberty, focusing on diagnostic challenges. The review is written from the perspective of the case of an 11.5-year-old girl who was referred to our clinic for progressive, rapid onset clitoromegaly, and was then diagnosed with a complex genetic form of DSD that led to abnormal testosterone production from a dysgenetic gonad at onset of puberty. Her genetic workup revealed a unique translocation of an abnormal duplicated Y-chromosome to a deleted chromosome 9, including the Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene. LEARNING OBJECTIVES: Identify the precise pathophysiologic mechanisms leading to virilization in girls at puberty considering that virilization at puberty may be the first manifestation of an endocrine active tumor or a disorder/difference of sex development (DSD) that remained undiagnosed before and may be life-threatening. Of the DSDs, nonclassical congenital adrenal hyperplasia occurs most often.Provide a step-by-step diagnostic workup plan including repeated and expanded biochemical and genetic tests to solve complex cases.Manage clinical care of a girl virilizing at puberty using an interdisciplinary team approach.Care for complex cases of DSD manifesting at puberty, such as the presented girl with a Turner syndrome-like phenotype and virilization resulting from a complex genetic variation.

Premature Adrenarche in Girls Characterized By Enhanced 17,20-Lyase and 17ß-Hydroxysteroid Dehydrogenase Activities.

CONTEXT: Girls with premature adrenarche (PA) may have a higher risk of developing polycystic ovary syndrome (PCOS) and metabolic syndrome. The biological purpose of adrenarche is unknown and the role of novel biosynthetic pathways remains unclear. OBJECTIVE: To compare the urinary steroid metabolome and enzyme activities of girls with PA to age-matched control girls and to published steroid values of girls with normal adrenarche and of women with PCOS and their newborn daughters. DESIGN: Prospective observational study from 2009 to 2014. SETTING: Academic pediatric endocrinology referral center. PARTICIPANTS: Twenty-three girls with PA and 22 healthy, age-matched girls. MAIN OUTCOME MEASURES: Steroid metabolites in 24-hour urine samples, including 4 progesterones, 5 corticosterones, aldosterone, 13 androgens, 2 estrogens, 14 glucocorticoids, and enzyme activities represented by metabolite ratios. RESULTS: Girls with PA had a higher body mass index (mean standard deviation scores 0.9 vs -0.3, P = 0.013). Androgen excretion was higher in PA girls than in control girls (median 3257 nmol/24 hours vs 1627 nmol/24 hours, P < 0.001), in particular metabolites from alternate androgen pathways. The amount of progesterone, corticosterone, aldosterone, estrogen, and cortisol metabolites were similar between groups. Activities of 17ß-hydroxysteroid-dehydrogenase and of 17,20-lyase were higher in girls with PA. Activities of 3ß-hydroxysteroid-dehydrogenase, 21-hydroxylase, and 5α-reductase activity were not different between groups, in contrast to published results on girls with normal adrenarche or PCOS females. CONCLUSIONS: Metabolites and enzymes involved in alternate androgen pathways appear to be markers of PA. Prospective studies should assess whether steroid production in PA also differs from adrenarche at normal timing and persists into adulthood.

Relationships among diet, physical activity, and dual plane dual-energy X-ray absorptiometry bone outcomes in pre-pubertalgirls.

In pre-pubertal girls, nutrient intakes and non-aquatic organized activity were evaluated as factors in vertebral body bone mass, structure, and strength. Activity, vitamin B12, and dietary fiber predicted bone outcomes most consistently. Exercise and vitamin B12 appear beneficial, whereas high fiber intake appears to be adverse for vertebral body development. PURPOSE: Childhood development sets the baseline for adult fracture risk. Most studies evaluate development using postero-anterior (PA) dual-energy X-ray absorptiometry (DXA) areal bone mineral density, bone mineral content, and bone mineral apparent density. In a prior analysis, we demonstrated that PA DXA reflects posterior element properties, rather than vertebral body fracture sites, such that loading is associated with subtle differences in vertebral body geometry, not 3D density. The current analysis is restricted to pre-pubertal girls, for a focused exploration of key nutrient intakes and physical activity as factors in dual plane indices of vertebral body geometry, density, and strength. METHODS: This cross-sectional analysis used paired PA and supine lateral (LAT) lumbar spine DXA scans to assess "3D" vertebral body bone mineral apparent density (PALATBMAD), "3D" index of structural strength in axial compression (PALATIBS), and fracture risk index (PALATFRI). Diet data were collected using the Youth/Adolescent Questionnaire (YAQ, 1995); organized physical activity was recorded via calendar-based form. Pearson correlations and backward stepwise multiple linear regression analyzed associations among key nutrients, physical activity, and bone outcomes. RESULTS: After accounting for activity and key covariates, fiber, unsupplemented vitamin B12, zinc, carbohydrate, vitamin C, unsupplemented magnesium, and unsupplemented calcium intake explained significant variance for one or more bone outcomes (p < 0.05). After adjustment for influential key nutrients and covariates, activity exposure was associated with postero-anterior (PA) areal bone mineral density, PA bone mineral content, PA width, lateral (LAT) BMC, "3D" bone cross-sectional area (coronal plane), "3D" PALATIBS, and PALATFRI benefits (p < 0.05). CONCLUSIONS: Physical activity, fiber intake, and unsupplemented B12 intake appear to influence vertebral body bone mass, density, geometry, and strength in well-nourished pre-pubertal girls; high fiber intakes may adversely affect childhood vertebral body growth.

[The acoustic changes of the voice in the singing boys during the permutation period].

The present study was based on the assumption that the determination of the fundamental frequency (Fo) of the speech by means of computer-assisted acoustic analysis makes it possible to detect the onset of vocal mutation in the singing boys. A total of 30 singing boys were available for the examination. They were allocated to two groups. Group 1 was comprised of 15 boys at the age between 11 years 10 months and 12 years 4 months. Group 2 consisted of 15 boys aged between 12 years 10 months and 13 years 2 months. All the participants of the study underwent an acoustic test in combination with indirect laryngoscopy. It was shown that fundamental frequency of the speech in the boys of group 2 was significantly lower than in group 1. The difference amounted to two half-tones and could be regarded as the onset of vocal pre-mutation. It is concluded that the acoustic analysis of the speech should be employed to determine the time of vocal pre-mutation in the singing boys. The singing teachers can use this method all by themselves.

Desenvolvimento sexual e maturação puberal / Sexual and puberal development

Os fenômenos do desenvolvimento sexual e puberal são eventos progressivos e coordenados. Dependem de fatores cromossômicos - gênicos, gonadais e hormonais. Tais eventos nos indivíduos do sexo masculino e feminino, sendo sincrônicos, permitirão um conveniente desenvolvimento sexual e puberal. Analisar tais fenômenos é o propósito deste estudo.(AU)

The sexual and puberal modifications are coordinate and progressive during differents life phases. Many factors are involved like genic-chromosomic, gonadal and hormonal. Those events that occurred in males and females are synchronous and to create a perfect development. Our proposal is review those situations.(AU)

Premature adrenarche--a common condition with variable presentation.

Adrenarche refers to a maturational increase in the secretion of adrenal androgen precursors, mainly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In premature adrenarche (PA), clinical signs of androgen action appear before the age of 8/9 years in girls/boys, concurrently with the circulating DHEA(S) concentrations above the usually low prepubertal level. The most pronounced sign of PA is the appearance of pubic/axillary hair, but also other signs of androgen effect (adult type body odor, acne/comedones, greasy hair, accelerated statural growth) are important to recognize. PA children are often overweight and taller than their peers, and the higher prevalence of PA in girls than in boys is probably explained by higher female adiposity and peripheral DHEA(S) conversion to active androgens. PA diagnosis requires exclusion of other causes of androgen excess: congenital adrenal hyperplasia, androgen-producing tumors, precocious puberty, and exogenous source of androgens. PA has been linked with unfavorable metabolic features including hyperinsulinism, dyslipidemia, and later-appearing ovarian hyperandrogenism. Although this common condition is usually benign, PA children with additional risk factors including obesity should be followed up, with the focus on weight and lifestyle. Long-term follow-up studies are warranted to clarify if the metabolic changes detected in PA children persist until adulthood.

Study protocol: the Childhood to Adolescence Transition Study (CATS).

BACKGROUND: Puberty is a multifaceted developmental process that begins in late-childhood with a cascade of endocrine changes that ultimately lead to sexual maturation and reproductive capability. The transition through puberty is marked by an increased risk for the onset of a range of health problems, particularly those related to the control of behaviour and emotion. Early onset puberty is associated with a greater risk of cancers of the reproductive tract and cardiovascular disease. Previous studies have had methodological limitations and have tended to view puberty as a unitary process, with little distinction between adrenarche, gonadarche and linear growth. The Childhood to Adolescence Transition Study (CATS) aims to prospectively examine associations between the timing and stage of the different hormonally-mediated changes, as well as the onset and course of common health and behavioural problems that emerge in the transition from childhood to adolescence. The initial focus of CATS is on adrenarche, the first hormonal process in the pubertal cascade, which begins for most children at around 8 years of age. METHODS/DESIGN: CATS is a longitudinal population-based cohort study. All Grade 3 students (8-9 years of age) from a stratified cluster sample of schools in Melbourne, Australia were invited to take part. In total, 1239 students and a parent/guardian were recruited to participate in the study. Measures are repeated annually and comprise student, parent and teacher questionnaires, and student anthropometric measurements. A saliva sample was collected from students at baseline and will be repeated at later waves, with the primary purpose of measuring hormonal indices of adrenarche and gonadarche. DISCUSSION: CATS is uniquely placed to capture biological and phenotypic indices of the pubertal process from its earliest manifestations, together with anthropometric measures and assessment of child health and development. The cohort will provide rich detail of the development, lifestyle, external circumstances and health of children during the transition from childhood through to adolescence. Baseline associations between the hormonal measures and measures of mental health and behaviour will initially be examined cross-sectionally, and then in later waves longitudinally. CATS will make a unique contribution to the understanding of adrenarche and puberty in children's health and development.

Puberty in children born small for gestational age.

Small for gestational age (SGA) children are more prone to have precocious pubarche and exaggerated precocious adrenarche, an earlier onset of pubertal development and menarche, and faster progression of puberty than children born of appropriate for gestational age (AGA) size. The majority of studies investigating the onset of puberty in children born SGA and AGA established that, although puberty begins at an appropriate time (based on chronological age and actual height) in SGA children, onset is earlier relative to AGA children. Evaluating pubertal growth in SGA children, a more modest bone age delay from chronological age at the onset of puberty and more rapid bone maturation during puberty compared to AGA children were reported. Peak height velocity in adolescence is reached at an earlier pubertal stage and lasts for a shorter period in children born SGA than in those born AGA. These differences lead to an earlier fusion of the growth plates and a shorter adult height. The pathophysiological mechanism underlying the unique pubertal growth pattern of children born SGA remains unclear. However, it seems that this is not only related to birth weight, gestational age, adiposity or obesity, but that there may also be an influence of rapid weight gain in early childhood on pubertal onset: excess weight gain in childhood may be related to central adiposity, decreased insulin sensitivity, and increased IGF-I levels and might thus predispose to precocious pubarche.

Absent adrenarche in children with hypopituitarism: a study based on urinary steroid metabolomics.

BACKGROUND: Up to now, the regulation of adrenarche remains a myth although ACTH may possibly play an important role. METHODS: Urinary steroid profiling by gas chromatography-mass spectrometry was used to study non-invasively the adrenarchal steroid metabolome in 13 children aged 6-16 years with partial or complete hypopituitarism (HP) whose ACTH/cortisol axis was affected and compared it with 24 healthy age-matched controls. The sum of DHEA, 16α-hydroxy-DHEA and 3ß,16α,17ß-androstenetriol served as markers for adrenarche parameters (AP). The excretion rates of major urinary cortisol metabolites were also determined. RESULTS: The excretion rates for AP were significantly lower for the HP subjects than for the controls (p < 0.001). After dividing the HP group into a subgroup treated with hydrocortisone (HC) and an HC-untreated subgroup, a significant difference for AP remained for each subgroup when compared to the control group (p < 0.001 and p = 0.045, respectively). Treatment with HC had no influence on AP. CONCLUSION: The data imply indirectly a significant contribution of ACTH to the regulation of adrenarche. Our results also signify important diagnostic information: absent adrenarche can be indicative of ACTH deficiency.

Very premature pubarche in girls is not a pubertal variant.

Premature pubarche (PP) in girls is considered to be a benign phenomenon and is the clinical expression of premature adrenarche. Since it does not usually increase the risk of either abnormalities in pubertal development or a reduced final adult height, a non-interventional approach is generally adopted after exclusion of non-classical (NC)congenital adrenal hyperplasia (CAH). Extremely premature pubarche is nevertheless not a pubertal variant. We here report two cases of adrenocortical tumors (ACT) for which precocious pubarche was the initial sign. This report suggests that premature pubarche is not always a mere pubertal variant and that a delay in the etiological diagnosis can be harmful. Therefore, pubarche before the age of four years should be considered as a feature of ACT or NC CAH until proven otherwise.

Adrenarche in nonhuman primates: the evidence for it and the need to redefine it.

Adrenarche is most commonly defined as a prepubertal increase in circulating adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfo-conjugate (DHEAS). This event is thought to have evolved in humans and some great apes but not in Old World monkeys, perhaps to promote brain development. Whether adrenarche represents a shared, derived developmental event in humans and our closest relatives, adrenal androgen secretion (and its regulation) is of considerable clinical interest. Specifically, adrenal androgens play a significant role in the pathophysiology of polycystic ovarian disease and breast and prostate cancers. Understanding the development of androgen secretion by the human adrenal cortex and identifying a suitable model for its study are therefore of central importance for clinical and evolutionary concerns. This review will examine the evidence for adrenarche in nonhuman primates (NHP) and suggest that a broader definition of this developmental event is needed, including morphological, biochemical, and endocrine criteria. Using such a definition, evidence from recent studies suggests that adrenarche evolved in Old World primates but spans a relatively brief period early in development compared with humans and some great apes. This emphasizes the need for frequent longitudinal sampling in evaluating developmental changes in adrenal androgen secretion as well as the tenuous nature of existing evidence of adrenarche in some species among the great apes. Central to an understanding of the regulation of adrenal androgen production in humans is the recognition of the complex nature of adrenarche and the need for more carefully conducted comparative studies and a broader definition in order to promote investigation among NHP in particular.

Premature adrenarche.

Premature adrenarche refers to the presence of secondary sexual hair in girls younger than 8 years old and boys younger than 9 years old. It is a relatively common presentation to paediatricians and is more frequent in girls than boys. It is a benign diagnosis, but other causes of androgen excess such as congenital adrenal hyperplasia or adrenal tumours should be excluded first. In conjunction with history and clinical examination, first line investigations should include determination of serum androgen concentrations, along with bone age, proceeding to synacthen stimulation test (for 17OHP levels) and adrenal ultrasound if indicated. The phenotype of premature adrenarche varies considerably between populations but may be associated with low birth weight, insulin resistance, adverse cardio-metabolic risk and progression to polycystic ovarian syndrome in some populations. In the majority of cases, no specific treatment is recommended, but where there is a history of low birth weight, with associated insulin resistance, intervention with the insulin sensitising agent metformin may be considered on a case by case basis.

Diagnostic work-up of 449 consecutive girls who were referred to be evaluated for precocious puberty.

OBJECTIVE: A decrease in age at pubertal onset has been observed internationally. The aim of this study was to describe a large cohort of Caucasian girls referred with signs of early puberty according to etiology and compare biochemical characteristics. METHODS: In this single-center study, we included 449 consecutive Caucasian girls who were referred with signs of early puberty during the years 1993-2009. We evaluated pubertal stage, height, weight, and bone age. FSH, LH, estradiol, and inhibin B were determined, and a standard GnRH test was performed. Brain magnetic resonance imaging was performed to rule out pathologies. RESULTS: During the period from 1993-2008, we found an increase in the number of girls in most diagnostic groups. Of 449 girls, 88 had central precocious puberty (CPP), and 12 of these had an organic origin. A total of 129 had early-normal variant (8-9 yr), 69 had premature thelarche, and 49 premature adrenarche. Receiver operating characteristic analyses revealed that basal LH was superior in predicting the maximal LH level during GnRH testing in comparison with FSH, estradiol, and inhibin B levels. Basal LH levels were above the age-related 2 sd in 26.2, 19.6, 65.1, and 75.0% of girls with, respectively, early-normal variant, premature thelarche, idiopathic CPP, and organic CPP, but LH levels below the detection limit were also seen among girls with a pubertal GnRH test. CONCLUSION: We observed an increasing number of girls referred because of early pubertal signs. An elevated basal LH was highly predictive of a pubertal GnRH test result, whereas a low LH did not exclude central pubertal activation.

[The sebaceous gland]. / Die Talgdrüse.

The development and function of the sebaceous gland in the fetal and neonatal periods appear to be regulated by maternal androgens and by endogenous steroid synthesis, as well as by other morphogens. The most apparent function of the glands is to excrete sebum. A strong increase in sebum excretion occurs a few hours after birth; this peaks during the first week and slowly subsides thereafter. A new rise takes place at about age 9 years with adrenarche and continues up to age 17 years, when the adult level is reached. The sebaceous gland is a target organ but also an important formation site of hormones, and especially of active androgens. Hormonal activity is based on an hormone (ligand)-receptor interaction, whereas sebocytes express a wide spectrum of hormone receptors. Androgens are well known for their effects on sebum excretion, whereas terminal sebocyte differentiation is assisted by peroxisome proliferator-activated receptor ligands. Estrogens, glucocorticoids, and prolactin also influence sebaceous gland function. In addition, stress-sensing cutaneous signals lead to the production and release of corticotrophin-releasing hormone from dermal nerves and sebocytes with subsequent dose-dependent regulation of sebaceous nonpolar lipids. Among other lipid fractions, sebaceous glands have been shown to synthesize considerable amounts of free fatty acids without exogenous influence. Atopic dermatitis, seborrheic dermatitis, psoriasis and acne vulgaris are some of the disease on which pathogenesis and severity sebaceous lipids may or are surely involved.

Hypogonadism in females with Prader-Willi syndrome from infancy to adulthood: variable combinations of a primary gonadal defect and hypothalamic dysfunction.

OBJECTIVE: The variable hypogonadism in Prader-Willi syndrome (PWS) has generally been attributed to hypothalamic dysfunction. Recent studies have documented primary testicular dysfunction in PWS males. Our aims were to characterize sexual development and reproductive hormones in PWS females and to investigate the etiology of hypogonadism. DESIGN: A cross-sectional study. METHODS: Physical examination was performed on 45 PWS females (aged 6 weeks to 32 years) and blood samples were obtained for hormonal analyses. RESULTS: Age of onset and progression of puberty varied; most adults had incomplete sexual development. Spontaneous menarche was reported in four (aged 15-30 years) but all had subsequently developed secondary amenorrhea or oligomennorrhea. Anti-Mullerian hormone levels were within the normal range in all age groups. Inhibin B was consistently low or undetectable; only five women had levels in the low-normal range (20-54 pg/ml). LH was normal in most children, but low (<1.0 IU/l) in 9 of 15 adults. FSH was within the normal range for age in most children, but low (<0.5 IU/l) in 10 and high in four adults. Estradiol levels were normal-low and androgen levels were normal in the majority. CONCLUSIONS: Pubertal development in PWS females, as in males, is characterized by normal adrenarche, pubertal arrest, and hypogonadism due to variable combinations of a unique primary gonadal defect and hypothalamic dysfunction.

Girls with premature adrenarche have accelerated early childhood growth.

OBJECTIVE: To evaluate the effect of premature adrenarche (PA) on prepubertal growth. STUDY DESIGN: The prepubertal growth of 54 girls with PA and 52 control girls was analyzed retrospectively. Birth measures were noted, and childhood length/height and weight were measured annually until age 5 years and at the current visit (at a median age of 7.6 years). The growth variables were correlated with serum insulin-like growth factor (IGF)-1, dehydroepiandrosterone sulfate, and insulin concentrations. RESULTS: There were no significant differences in birth length or weight standard deviation scores (SDSs) between the 2 study groups. The girls with PA demonstrated a significant length SDS increment during the first 2 years of life (median +1.0 SDS; P < .001). Compared with controls, they were taller (median current height 1.2 vs 0 SDS; P < .001) and gained more weight throughout childhood. The difference in weight-for-height became significant at a later age compared with the difference in height. Median serum IGF-1 concentration adjusted for both age and body mass index SDS was higher in the PA group (24 vs 19 nmol/L; P < .031). CONCLUSIONS: PA was not associated with small birth size in our population. Girls with PA had enhanced growth already in early childhood, which was not explained by weight gain. Enhanced IGF-1 production may contribute to the prepubertal growth acceleration in PA.

Expression of the IGF and the aromatase/estrogen receptor systems in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche.

Adrenarche is a process of postnatal sexual maturation occurring in higher primates, in which there is an increase in the secretion of adrenal androgens. It is the consequence of a process of postnatal organogenesis characterized by the development of a new zone in the adrenal cortex, the zona reticularis (ZR). The mechanism of this phenomenon remains poorly understood, suggesting that it might be a multifactorial event. A relationship between circulating IGF-I, insulin sensitivity, and adrenal androgens has been postulated. Boys and girls have different patterns of changes in insulin sensitivity at puberty, perhaps secondary to differences in the estrogen milieu. Estrogen effects may also play a role in premature adrenarche. Peripheral or local IGF-1 actions could regulate adrenal progenitor cell proliferation and migration. Since adrenal progenitor cells as well as IGF-I and the IGF-R1 are located in the outer zone of the adrenal cortex during childhood and adolescence, this peripheral cell layer, below the capsule, may contain undifferentiated progenitor cells. Therefore, the IGF-R1 signaling pathway might positively modulate the proliferation and migration of adrenal progenitor cell to stimulate the development of adrenal zones, including ZR. However, no evidence of a direct action of IGF-I on ZR was found. In addition, a role for estrogens in the ontogenesis of ZR is suggested by the presence of aromatase (CYP19) in the subcapsular zona glomerulosa and in the adrenal medulla. Estrogens produced locally could act on ZR by interacting with estrogen receptor beta (ERbeta), but not alpha, and membrane estrogen receptor GPR-30. An estradiol-induced increase in DHEA/cortisol ratio was indeed seen in cultures of adrenocortical cells from post-adrenarche adrenals. In summary, several lines of evidence point to the action of multiple factors, such as local adrenal maturational changes and peripheral metabolic signals, on postnatal human adrenal gland ZR formation.

Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation.

Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the adrenal cortex. Cells could then migrate to differentiate the zona glomerulosa (ZG) and zona fasciculata (ZF) during fetal life, and the ZR during postnatal life. After adrenarche, there are detectable increases in circulating DHEA and DHEA-S. Adrenarche could result from an increase in 17,20-lyase activity of P450c17 secondary to high levels of cytochrome b(5) expression, and from a decrease in 3betaHSD2 expression along with an increase in the expression of SULT2A1 in the ZR. The GH-IGF system and insulin, among other factors, might also modulate adrenal androgen production. Furthermore, high concentrations of estradiol enhance basal and ACTH-stimulated DHEA-S production, while aromatase expression was observed in the human adrenal medulla but not in the ZR, suggesting that estrogens produced in the adrenal medulla might be involved in the regulation of androgen production in the ZR. Premature adrenarche might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as well as with insulin resistance in both sexes. However, many questions remain, transforming adrenal androgens into markers of diseases important for human health.