This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ibáñez, L. Articles by Saenger, P. Search for Related Content PubMed PubMed Citation Articles by Ibáñez, L. Articles by Saenger, P.

Premature Adrenarche—Normal Variant or Forerunner of Adult Disease?¹

Endocrinology Unit, Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain 08950 (L.I.); Division of Pediatric Endocrinology (J.D.-N., P.S.), Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York 10467; and Hormonal Laboratory (N.P.), Hospital Materno-Infantil, Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain 08035

	Abstract

Top Abstract I. Adrenarche II. Premature Adrenarche III. Conclusions References

 
Adrenarche is the puberty of the adrenal gland. The descriptive term pubarche indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 yr in girls and 9 yr in boys.

The chief hormonal product of adrenarche is dehydroepiandrosterone (DHEA) and its sulfated product DHEA-S. The well documented evolution of adrenarche in primates and man is incompatible with either a neutral or harmful role for DHEA and implies most likely a positive role for some aspect of young adult pubertal maturation and developmental maturation. Premature adrenarche has no adverse effects on the onset and progression of gonadarche in final height.

Both extra- and intraadrenal factors regulate adrenal androgen secretion. Recent studies have shown that premature adrenarche in childhood may have consequences such as functional ovarian hyperandrogenism, polycystic ovarian syndrome, and insulin resistance in later life, sometimes already recognizable in childhood or adolescence. Premature adrenarche may thus be a forerunner of syndrome X in some children. The association of these endocrine-metabolic abnormalities with reduced fetal growth and their genetic basis remain to be elucidated.

I. Adrenarche

A. Introduction

B. Definition

C. Hormonal basis of adrenarche and reference data for steroid hormone levels in adrenarche

D. Biological role of adrenarche

E. Control of adrenarche

F. Adrenarche and gonadarche

II. Premature adrenarche

A. Definition

B. Pathophysiological basis

C. Clinical features

D. Adrenal androgens in premature adrenarche

E. Differential diagnosis

F. Timing of puberty and final height

G. Postpubertal outcome

H. Patterns of insulin secretion

I. Lipid levels in premature adrenarche

J. Acanthosis nigricans

K. Future avenues of investigation

L. Premature adrenarche, hyperinsulinism, and ovarian dysfunction: possible relation to reduced fetal growth

III. Conclusions

	I. Adrenarche

Top Abstract I. Adrenarche II. Premature Adrenarche III. Conclusions References

 
A. Introduction
Adrenarche is the "puberty" of the adrenal gland. It is characterized by the activation of adrenal androgen production and by impressive increases in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), both products of the zona reticularis of the adrenal gland (see Fig. 1).

View larger version (92K): [in this window] [in a new window]   Figure 1. Sections through the adrenal glands of a 6-month old infant (left) and of an adult man (right). While the infant has no reticularis zone, the reticularis zone is present in the adult adrenal (see also Fig. 3). [Reprinted with permission from W. Bloom, D.W. Fawcett: Textbook of Histology, ed. 9. W.B. Saunders Co., Philadelphia, 1986, p 461 (323 )].

The descriptive clinical term pubarche indicates the appearance of pubic hair, which may be accompanied by axillary hair. This process is considered premature if it occurs before age 8 in girls and before 9 in boys (4, 5, 6).

C. Hormonal basis of adrenarche and reference data for steroid hormone levels in adrenarche
Studies by several investigators (1, 7, 8, 9, 10, 11, 12) showed that adrenarche is characterized by dramatic increases in urinary 17-ketosteroids and serum levels of dihydrotestosterone, DHEA, and DHEAS (13). Androstenedione, a zona fasciculata product, and 11-hydroxyandrostenedione (14, 15), a zona reticularis product, do not rise during adrenarche. These increases take place in girls and boys between 6 and 8 yr of age, approximately 2 yr before the onset of gonadal maturation and puberty (gonadarche) (10, 11, 12, 16, 17, 18). Cortisol concentration, production, and excretion remain constant (19).

Absence of normative data for adrenal steroidogenesis in children hampered characterization of the endocrine effects of adrenal androgens in the past. Over the past 10 yr, reference data for steroid hormones at baseline and after standard ACTH stimulation have been published and demonstrate a substantial breadth of normalcy as well as gender differences (20, 21). The most widely used protocol for the ACTH stimulation test (250 µg Cortrosyn iv or im) eschews dexamethasone suppression before ACTH testing. Responses to ACTH stimulation change throughout childhood, with definite age-, sex-, and pubertal stage-dependent differences in resulting steroid levels. Ethnic origin may also influence ACTH response pattern (22, 23). An enhanced adrenal sensitivity to ACTH and additional alterations in the metabolic clearance rates of 17- hydroxyprogesterone (17-OHP) or progesterone are characteristic of obese adults but have not been conclusively observed in children (24). In careful longitudinal studies the progressive increase in serum concentrations of DHEA and DHEAS in healthy boys and girls that begins at the age of 6 to 8 yr roughly parallels an increase in skeletal age (25, 26, 27, 28, 29, 30, 31, 32) (Fig. 2). Adrenal androgen levels rise steadily up to age 18–20 yr. During this period a 20-fold increase in DHEAS concentration is accompanied by an increase in the secretion of 17-ketosteroids, especially deoxy C19 steroids. Because androstenedione can be formed peripherally from DHEAS as well as directly by the gonads, circulating levels do not necessarily reflect adrenal production rates. A surrogate marker for adrenal production of androstenedione is 11-hydroxyandrostenedione (15). The enzyme necessary for its formation is expressed only in the adrenal gland; this steroid is therefore specific for the adrenal cortex.

View larger version (31K): [in this window] [in a new window]   Figure 2. Serum DHEAS concentrations in normal boys and girls. Each entry represents a simple value: serial values in children are connected by lines. The area between the two vertical lines encompasses the usual age of onset of puberty in girls, while the shaded area encompasses the usual age of onset of puberty in boys. [Reprinted with permission from S. Korth-Schutz et al.: J Clin Endocrinol Metab 42:1005–1013, 1976 (27 ) © The Endocrine Society.]

For clinical purposes, DHEA and particularly DHEAS are useful markers for adrenal androgen secretion. Based on several studies, levels of DHEAS above 40–50 µg/dl are considered to be consistent with the advent of adrenarche (34, 35).

Numerous studies suggest that the adrenal androgens, DHEA and DHEAS, emanate chiefly from the zona reticularis (36, 37, 38). Recent elegant studies by Endoh et al. (39), using dispersed adrenal cells, identify the zona reticularis, the innermost layer of the adrenal cortex, as the site of biosynthesis of DHEA and DHEAS. The zona reticularis is theorized to be the morphological equivalent of the fetal zone of the adrenal cortex. The fetal zone virtually disappears in the first few months after birth, and production of DHEA and DHEAS virtually ceases, only to resume some 6 yr later (40, 41, 42, 43, 44).

D. Biological role of adrenarche
Growth patterns have been investigated in normal children going through adrenarche. A small but significant growth spurt has been found by two independent investigators to occur between 6.5 and 8.5 yr of age—exactly the age when adrenarche occurs (45, 46). Others have been unable to demonstrate a midchildhood growth spurt (47). Treatment of a child with adrenal hyperplasia with oral DHEA at a dose sufficient to raise DHEAS into the normal range increased linear growth and caused growth of pubic hair, although puberty did not occur (48). In children with precocious puberty who are being treated with GnRH agonists for gonadotropin suppression, DHEA concentrations were found to correlate well with the rate of skeletal maturation (35).

Adrenal androgens also lower serum levels of sex hormone binding globulin (SHBG). This may represent an effect of adrenal androgens on the tempo of the pubertal process through the augmentation of biologically available free testosterone (49). Other investigators found, even with short-term elevation of plasma testosterone levels to 130 ng/dl, only a slight depression of SHBG (50). The well known gender-dependent differences in postnatal SHBG may also suggest a role for prenatal induction in SHBG levels (51).

The event of adrenarche occurs only in humans and higher primate species (chimpanzee, gorilla) that have a long childhood preceding the advent of puberty (52, 53, 54). While the Rhesus monkey, Cynomolgus monkey, and the crab-eating macaque have low levels of DHEA that are at their highest in the newborn and decline thereafter with no discernible adrenarcheal process (55, 56), their DHEAS appears to originate from a persistent fetal zone rather than from a zona reticularis arising at adrenarche (57). On the other hand, the increase of adrenal androgen levels with age in the chimpanzee closely resembles adrenarche in man. The rise in DHEA levels in the chimpanzee preceding gonadal maturation is also comparable to that in man: DHEA levels begin to rise by 5 yr of age, exactly 2 yr before testosterone levels begin to increase in that species.

Androgens of adrenal origin have been postulated to initiate activation of the hypothalamic/pituitary/gonadal axis in puberty; witness the fact that children untreated or poorly treated for congenital adrenal hyperplasia, who consequently have markedly increased androgens, enter central puberty at an earlier or even precocious age (38). The persistent high levels of adrenal androgens in the Rhesus monkey after birth may therefore play a contributory role in its early sexual maturation, whereas the low level of adrenal androgens before adrenarche in man and chimpanzee may be one of several factors in the relatively delayed onset of puberty in these species (53). The role of adrenal androgens in sexual maturation doesn’t apply broadly, however. The rat, for example, does not make DHEA or its sulfate and yet has an early puberty.

The well documented evolution of adrenarche in primates and man is incompatible with either a neutral or harmful role for DHEA but most probably implies a positive role for some aspect of young adult health and reproduction (57).

E. Control of adrenarche
1. The role of the zona reticularis in adrenal androgen production. The adrenal gland of the young child between 1 to 6 yr of age makes predominantly cortisol, a C21 steroid, but virtually no androgens (C19 steroids) (58, 59). The zona reticularis, not perceptible in children under 6, later recapitulates the secretory pattern of the fetal zone, forming DHEA and DHEAS (58, 59, 60, 61, 62, 63, 64, 65, 66, 67). Since the zona reticularis is the only adrenal zone with sulfotransferase activity, DHEAS is a good marker for functional activity of the zona reticularis (62, 63, 68). Both DHEA and DHEAS are products of the 5 pathway (see Fig. 3). The development of the zona reticularis correlates closely with the increasing DHEAS production (31), which is due to low expression of 3ß-hydroxysteroid dehydrogenase (3ß-HSD) activity (14). While the major source of sulfation of DHEA is obviously the adrenal gland, other tissues also have limited sulfotransferase activity (69). The production rate for DHEAS is about 31 mg/day in young men and 19 mg/day for young women, making this the most abundant steroid in humans. The half-life of DHEAS is between 9 and 11 h, whereas it is 30–60 min for the unconjugated DHEA (67). The plasma concentration of DHEAS exhibits a high correlation with urinary 17-ketosteroids and can be used to assess adrenal androgen production rates (67). DHEAS, the steroid hormone in the greatest concentration in the human circulation, can also be synthesized from other sulfated precursors, such as cholesterol sulfate and pregnenolone sulfate (69). Plasma DHEAS concentrations show only minor circadian fluctuations, while those of DHEA seem to follow a circadian pattern similar to that of cortisol (70).

View larger version (21K): [in this window] [in a new window]   Figure 3. Scheme of steroidogenic pathways. 17-Hydroxylase and 17,20-lyase are activities of cytochrome P450C17. 3HSD, 3ß-Hydroxysteroid dehydrogenase; DOC, 11-deoxycorticosterone; S, 11-deoxycortisol; C21, P450C21; c11, P450C11. Note that in the adrenal, little androstenedione is formed from 17OH pregnenolone. Most androstenedione is derived from DHEA and through peripheral conversion.

Careful histological studies by Dhom (73) suggest that the appearance of adrenarche is associated with an increase in the thickness of the zona reticularis (Fig. 4). The zona reticularis begins to develop in foci at age 3 to 5 yr, and by age 7 to 8 yr it is usually present as a continuous zone, as the medullary capsule of the adrenal disintegrates at the same time. Growth of the zona reticularis is directly related to rises in DHEAS levels (Fig. 5). After a peak of adrenal androgen production at age 20 to 25, DHEAS, particularly, begins a steep, continuous decline (57), while serum levels of aldosterone and cortisol undergo relatively little change with age (57, 74, 75, 76).

View larger version (24K): [in this window] [in a new window]   Figure 4. Age at which focal islands of reticular tissue or a continuous reticular zone were found in a series of patients with sudden deaths who had not had an antecedent illness. [Reprinted with permission from G. Dhom: Beitr Pathol 150:357–377, 1973 (73 ).]

View larger version (16K): [in this window] [in a new window]   Figure 5. Relation of plasma DHEAS to growth of the zona reticularis and increase in adrenal volume with age. [Reprinted with permission from M. M. Grumbach et al.: In V. H. T. James et al. (eds) The Endocrine Function of the Human Adrenal Cortex. Serono Symposia 18. Academic Press, London, pp 583–612 (16 ).]

2. The Regulation of adrenal androgen secretion.
a. Extraadrenal factors.
Numerous endocrine signals endogenous and exogenous to the adrenal gland (37) have been proposed as stimuli of adrenal androgen secretion. Among those proposed as exogenous to the adrenal gland were PRL (77, 78), estrogen (79, 80, 81, 82, 83), epidermal growth factor (84), prostaglandins (85), angiotensin (86), GH (87), gonadotropins (88, 89), ß-lipotropin, ß-endorphin, and CRF (90, 91, 92). The adrenal cortex has a high level of PRL receptors in several species (93). In women with PRL-secreting tumors there is a correlation between PRL levels and DHEAS (94). GH receptors are present in the adrenal cortex (95, 96). Recently, administration of MK 0677, a nonpeptidyl compound that restores pulsatile GH secretion by the pituitary, was found to increase DHEAS levels in adults (97). To date, none of these factors has been conclusively identified as a regulator of adrenal androgen secretion of biological significance.

Patients with familial glucocorticoid deficiency due to mutations in the coding region of the ACTH receptor show not only low cortisol levels but also low DHEAS and androstenedione levels and a complete lack of adrenarche. Despite adequate glucocorticoid replacement, ACTH levels remain elevated (98).

ACTH and CRH as a dual control mechanism (99, 100) probably have a permissive role in the modulation of adrenal androgen secretion but are thought not to be the sole stimuli for the rise in adrenal androgen secretion (101). Another pituitary factor, "ACTH-like," which might stimulate adrenal androgen secretion was postulated previously by Mills et al. (8) and by Grumbach and co-workers (16). Based on studies in hypophysectomized, ACTH-replaced chimpanzees, Cutler and colleagues (101) developed the hypothesis that ⁵ androgen secretion is dependent upon a non-ACTH pituitary factor or that different ACTH requirements exist for maintenance of normal cortisol and adrenal androgen secretion. This hypothesis was strengthened by the clinical finding that in pediatric patients with Cushing’s syndrome due to central ACTH overproduction, there is generally no increase in DHEAS and DHEA above normal levels for chronological and bone age, despite the marked increase in cortisol secretion. Hauffa et al. (102) interpreted this observation as lending further support for their theory that there is yet another adrenal androgen-stimulating factor that may indeed be central (18). POMC-related peptides are elevated in pituitary adenomas of patients with Cushing’s disease (103, 104), yet DHEA and DHEAS levels are not elevated. Known POMC-related peptides do not appear to be the adrenal androgen-stimulating factor (104). POMC was believed to be the leading candidate for a glucocorticoid-suppressible adrenarche-stimulating factor. A human pituitary fraction containing a 60,000-dalton glycopeptide that is capable of stimulating the zona reticularis selectively in the dog has been described by Parker et al. (105). This fraction, sharing amino acids POMC_79–96 with human POMC, stimulated DHEA secretion without affecting cortisol secretion in an in vitro dog adrenal bioassay. In subsequent studies using human pituitary fractions and cultured human adrenal cells, it was identified by Parker et al. (106, 107) as central androgen-stimulating hormone (CASH). The synthesized 18-amino acid peptide, CASH-18, stimulated production of DHEA from cultured adult adrenal cells but had no effect on cortisol secretion. When POMC_79–96 was studied by three additional groups (108, 109, 110) with and without ACTH in cultured human fetal and adult adrenal cells, it had no demonstrable effect. No specific binding to human adrenocortical cells could be measured (109). This does suggest strongly that POMC_79–96 is not the elusive central androgen-stimulatory hormone in man. The fact that in an adenoma tissue sample from human Cushing’s disease, increased POMC (111) was not associated with elevated DHEA or DHEAS casts further doubt on the relevance of CASH in the initiation of adrenarche.

A change in nutritional status, measurable in the form of body mass index (BMI) increases, also appears to be an important physiological regulator of adrenarche regardless of individual adrenal androgen secretion, age, and developmental stage (112).

b. Intraadrenal factors.
As adrenarche represents a change in the pattern of adrenal-secretory response to ACTH, another theory for its biochemical foundation is that it is dependent on intraadrenal factors that control growth and differentiation of the zona reticularis, with concomitant changes in the activity of steroidogenic enzymes. Anderson (113) has formulated an attractive hypothesis relating adrenarche to the maturation of the zona reticularis as observed in the histological substrate by Dhom (73). According to this hypothesis the reticularis is exposed to high cortisol concentrations from the adjacent zona fasciculata. Gradually the innermost cells of the fasciculata start to respond to the very high cortisol levels by undergoing morphological and functional changes. Zonal and developmental changes of steroid enzyme activities, as described by Winter and colleagues (66, 114, 115), particularly increased activity of 17,20-lyase, sulfokinase, and sulfatase and reduced activity of 3ß-HSD, especially in the reticularis zone, would lead to production of more DHEA, DHEAS, and androstenedione in response to ACTH.

Adrenarche, thus, is characterized by a profound change in the degree and in the pattern of the adrenal secretory response to ACTH. The levels of 17-OH pregnenolone (17-OH Preg), DHEA, and DHEAS increase strikingly. Maturational increases in 17-hydroxylase and 17,20-lyase are seen together with a low activity of 3ß-HSD (116, 117, 118, 119), particularly in the developing zona reticularis.

Using adult human fasciculata and reticularis cells L’Allemand et al. (120) demonstrated that both insulin-like growth factors I and II (IGF-I and IGF-II) enhance steroidogenic enzyme activity of 17ß-hydroxylase and 3ß-HSD. ACTH receptor mRNA was also slightly increased, while mRNA for cytochrome P450_scc remained unchanged. Thus, IGF-I and -II mimic some of the changes observed in adrenarche; other effects, such as the increase in 3ß-HSD activity, are opposite to those typically observed at the time of adrenarche. The possible role of transforming growth factor-ß1 (TGF-1) in adrenarche is less clear. TGF-1 stimulates 3ß-HSD activity in adult human adrenal cells. A local diminution of TGF-1 production might be involved in the steroid hormone changes observed at adrenarche. The factor responsible for this reduction in TGF-1 expression remains to be elucidated (121). T-cells within the adrenal gland have direct cell-to-cell contact with epithelial cells of the adrenal zona reticularis; this provides a mechanism for immune system-mediated stimulation of androgen secretion in vitro. This establishes evidence for a non-ACTH-mediated mechanism of adrenocortical androgen regulation (122).

Thus, adrenal mass, pattern of intraadrenal blood flow, intraadrenal steroid concentrations, and immune system-mediated stimulation, together with enzymatic changes and changes in ACTH response, affect adrenal androgen production as adrenarche begins.

c. P450C17 and adrenarche.
An especially intriguing new, molecular genetic approach was suggested by the observation that increasing the molar ratio of isolated, purified electron donors, such as P450 oxidoreductase (OR) or cytochrome b5, to porcine P450C17 would increase the ratio of 17,20-lyase-to-hydroxylase activity (123, 124). Recent experiments by Miller and co-workers (125) with transfected cos-1 cells confirm that the expression of vectors encoding human OR and human P450C17 results indeed in a substantial increase in 17,20-lyase activity. However, it seems unlikely that adrenarche could result from a large increase in the expression of an electron donor, as the activity of adrenal cytochrome P450C21 (steroid 21-hydroxylase), which uses the very same electron donors, is unchanged during adrenarche (58).

Human cytochrome b5 acts principally as an allosteric effector that interacts primarily with the P450C17 OR complex to further stimulate 17,20-lyase activity. Complete absence of cytochrome b5, as described in a splicing mutation, may lead to low levels of androgen synthesis and even male pseudohermaphroditism (126).

Since the regulation of 17-hydroxylase and 17,20-lyase determines the degree or amount of precursor steroids that are converted to sex steroids, regulation of these two enzymatic steps coded by a single human gene for P450C17 is extremely important. The 17-hydroxylation of pregnenolone and progesterone and the subsequent cleavage (17, 20-lyase activity) of 17-OH Preg and 17-OHP are catalyzed by a single enzyme, cytochrome P450C17. In the testes, all precursor steroids are converted to sex steroids; the ratio of lyase to hydroxylase activity is therefore 1. In the human adrenal cortex, however, activity of these enzymes, as well as other enzymes, is under closely regulated control during development, which may determine timing as well as tempo of adrenarche. Previous studies have shown that a specific amino acid sequence is required for maintenance of 17,20-lyase activity (126, 127). Since the amino acid sequence of P450C17 cannot change with adrenarche, Zhang and co-workers postulated that a posttranslational modification of P450C17 could alter the ratio of hydroxylase to lyase activity (64).

Consistent with their hypothesis, these authors have found in an in vitro system using African green monkey kidney cells that the serine phosphorylation of cytochrome P450C17 by a cAMP-dependent kinase accounts for a large increase in 17,20-lyase activity (64). This process differs from the regulation of 17ß-hydroxylase activity, which is needed to produce cortisol throughout life. The 17,20-lyase enzyme is controlled independently in an age-dependent pattern. Early activation of this process increases 17,20-lyase activity. P450C17 is phosphorylated on serine and threonine residues by a cAMP-dependent protein kinase; phosphorylation of P450C17 increases lyase activity, while dephosphorylation virtually eliminates this activity. Hormonally regulated serine phosphorylation of human P450C17 suggests a possible mechanism for human adrenarche that would unify all clinical findings.

These studies do require independent confirmation, and altered phosphorylation of P450C17 has yet to be demonstrated in children at adrenarche or, for that matter, in children with premature adrenarche (119). Thus, the role of serine phosphorylation remains only a hypothesis until such a time as the kinase is cloned and activating mutations are found in families with polycystic ovary syndrome (PCOS) or premature adrenarche.

Hornsby cautions that an absence in the change of adrenal production of androstenedione makes it unlikely that adrenarche involves changes in 17,20-lyase activity of CYP17, the gene encoding for P450C17 (57), although it should be pointed out that physiological responses of ⁴ to ACTH are modest (20, 21). A quite simple explanation for the absence of a rise in androstenedione may be that the preferentially used ⁵ pathway in the adrenal, of course, bypasses androstenedione altogether (57).

While the physiological trigger for adrenarche and/or altered P450C17 hydroxylase and lyase activity is currently unknown, Zhang et al. (64) speculate that IGF-I and possibly also insulin are good candidates. Both insulin and IGF-I transmit their signals by initiating tyrosine autophosphorylation of the insulin/IGF-I receptors, while the phosphorylation of serine and threonine residues markedly diminishes signal transduction (128, 129, 130).

F. Adrenarche and gonadarche
The increase in adrenal androgens is not associated with an increase in sensitivity of gonadotropins to GnRH or with sleep-associated LH secretion characteristic of puberty; rather it occurs at an age when the hypothalamic/pituitary/gonadal axis is functioning at a lower level of activity and gonadarche has not yet occurred. Adrenarche and gonadarche are thus two separate maturational events (131). Timing of adrenarche in girls with Turner syndrome who do not undergo gonadarche is perfectly normal (132). Similarly, children with isolated gonadotropin deficiency will undergo normal adrenarche while children with adrenal insufficiency will not. In true isosexual central precocious puberty occurring before the age of 6 yr, there is generally no adrenarche, whereas in precocious puberty occurring after age 6 yr, adrenarche may be present (133). Boys treated for primary adrenal insufficiency have been noted to enter puberty at a normal age (134). Thus, adrenarche and gonadarche are independent events controlled by separate mechanisms (131) (see Table 1).

	II. Premature Adrenarche

Top Abstract I. Adrenarche II. Premature Adrenarche III. Conclusions References

Premature development of pubic hair with and without axillary hair and without other signs of virilization or puberty was first described by Wilkins (135) and was descriptively named premature pubarche. Some years later, other investigators suggested that the adrenal glands could be involved in the development of this condition and they named it, therefore, "precocious adrenarche" (136).

An increased frequency of premature adrenarche has been reported in children with cerebral dysfunction with a sex ratio close to 1 (138, 139), although children with premature adrenarche do not have more developmental or behavioral problems (140). Weight gain may be a trigger for adrenarche (112), and obesity has also been associated with a higher incidence of premature adrenarche (141, 142, 143).

Recent data suggest that girls seen by primary care practitioners in the United States show pubic hair and/or breast development at younger ages than stated above (144). In a cross-sectional study involving 17,077 girls, striking differences were detected in pubic hair development between black and white girls. At 6 yr of age, 9.5% and, at 8 yr of age, 34.3% of black girls had at least Tanner stage 2 pubic hair, whereas 1.4% and 7.7% of white girls, at these ages, had pubic hair. Although these observations might suggest a revision of the current criteria for referral of premature adrenarche patients, the data should be interpreted with caution, as there may have been a bias in self-referral of these patients to the pediatric practices. Furthermore, as no endocrine evaluations were carried out in the study, it is not known whether some of the girls included had pathological conditions accounting for the early appearance of pubertal milestones (144).

Pubarche after age 7 yr is often slowly progressive. However, that does not mean that it is normal. Evidence is emerging that premature pubarche may on occasion be a risk factor for subsequent reproductive endocrine system dysfunction (144A ).

B. Pathophysiological basis
Generally, premature adrenarche is secondary to an early isolated maturation of the adrenal gland (26, 30, 145, 146, 147). Adrenal androgens, particularly DHEA, DHEAS, androstenedione, and testosterone, are in most cases moderately increased for chronological age but fall within the expected range according to the pubertal stage of pubic hair (59, 145, 147, 148). In some patients, the early development of pubic hair is associated with normal androgen levels for chronological age, suggesting increased peripheral sensitivity (59, 145, 149). Lee et al. (150) described a family in whom adrenal androgen hypersecretion was transmitted as a dominant non-HLA-linked trait (150).

The cause of the adrenal oversecretion in premature adrenarche is currently unclear (151). Gonadotropins do not play a role in the development of premature adrenarche (152, 153) just as in normal adrenarche.

C. Clinical features
In typical or isolated premature adrenarche the appearance of pubic hair, which is usually dark, straight or curly, and coarse, is mostly limited to the labia majora in girls and thus may elude detection on casual examination in an obese girl. The development of pubic hair is non- to slowly progressive and may spread throughout the pubic area (154). Axillary hair growth may also be noted (6, 141). A mild hypertrichosis with fine hair over the extremities and back is much less frequently observed (141). Increased body odor, oily skin, and acne, usually in the form of a few microcomedones, may be present. Clitoral or penile enlargement are usually absent, and testicular and breast size remain at the prepubertal stage (155). Growth velocity may be increased, and moderately advanced bone maturation (<±2 SD is often present, but is generally correlated with the height age) (4, 141, 155, 156, 157).

D. Adrenal androgens in premature adrenarche
Although DHEA and DHEAS are relatively weak androgens, they serve as a substrate for the synthesis of more potent androgens, such as androstenedione and testosterone (158, 159). In premature adrenarche, baseline serum levels of DHEA, and to a lesser degree, those of androstenedione and testosterone as well as their urinary metabolites, the 17-ketosteroids, are in the range of those found in early puberty (6, 26, 33, 59, 145, 147, 148, 157, 160, 161, 162, 163) (Fig. 6). However, DHEAS levels may exceed those of pubertal controls (148, 162). Serum DHEAS concentrations can be suppressed to a greater extent after dexamethasone treatment, although the degree of suppression is highly variable and seems to be related to bone age (23).

View larger version (31K): [in this window] [in a new window]   Figure 6. Baseline plasma androgen levels in girls with premature appearance of pubic hair compared with age-matched controls. The enclosed areas represent the mean ± 2 SD levels in controls. 17-OHP, 17-Hydroxyprogesterone; 5 , androstenedione. [Modified with permission from R. Virdis et al.: Riv Ital Pediatr (IJP) 19:569–579, 1993 (160 ).]

The responses of the steroid precursors 17-OHP, 17-OH Preg, and 11-deoxycortisol to ACTH are between the prepubertal and adult range in more than 90% of children with premature adrenarche (145).

E. Differential diagnosis
Premature adrenarche is a diagnosis of exclusion. In those patients in whom pubic hair is accompanied by testicular, breast, or clitoral enlargement (atypical premature adrenarche), the strong possibility of precocious puberty or a virilizing adrenal or gonadal tumor must be ruled out (4, 141, 155). The possibility of iatrogenic androgen administration must also be kept in mind. A careful history and physical examination can potentially rule out these entities. In some cases, measurement of gonadotropins and gonadal steroids may be necessary (Table 2).

The incidence of mild defects of steroidogenesis among premature adrenarche patients is not well defined and ranges from about 0 to 40% of cases (144, 148, 167, 168, 169, 170, 171, 172, 173, 174). This discrepancy may be due to several factors. The ethnic origin of the patients is important and can partially explain the high variability of incidences reported. For example, in Ashkenazi Jews, the prevalence of late-onset congenital adrenal hyperplasia due to P450C21 deficiency has been calculated to be as high as 3.7% with a disease frequency of 1 in 27 (175). Conversely, the incidence of this enzymatic defect among Spanish children presenting with premature adrenarche is 7% (148). The number of subjects studied and the diversity of criteria adopted for diagnosis may also account for the differences.

Most patients with premature adrenarche due to late-onset congenital adrenal hyperplasia have clinical features characteristic of atypical premature adrenarche and present with elevated baseline hormone (17-OH Preg, 17-OHP, androstenedione, testosterone) levels. However, there is still controversy as to whether all children with premature adrenarche should undergo an ACTH stimulation test (250 µg Cortrosyn iv or im), based on the fact that, in some cases, baseline hormonal levels may be normal in mild errors of steroidogenesis (148, 168). We recommend ACTH testing in those children with ratios of bone age to statural age greater than 1, and/or elevated basal androgen levels, and/or signs of atypical premature pubarche (4, 155) (Fig. 7). Atypical premature adrenarche is characterized by bone age advancement (155), cystic acne, and signs of systemic virilization.

View larger version (26K): [in this window] [in a new window]   Figure 7. Differential diagnosis of elevated androgens in premature adrenarche. Algorithm for the hormonal diagnosis of premature adrenarche. Baseline androgen levels are assessed. Markedly elevated plasma androgen levels point toward tumor or Cushing’s syndrome (if cortisol levels are concomitantly elevated). Moderately elevated plasma androgen levels other than DHEAS indicate the need for an ACTH test to rule out congenital adrenal hyperplasia. If only plasma DHEAS is moderately elevated, the diagnosis of premature adrenarche is made.

The hormonal criteria for mild 3ß-HSD deficiency are still very controversial. Some 1–13% of children presenting with premature adrenarche and 3–50% of older female patients with hirsutism and menstrual disorders have been reported to have this enzymatic defect based on published hormonal criteria (179, 180). The molecular analysis of the type I and type II 3ß-HSD genes in children with premature adrenarche and hyperandrogenic women has failed to demonstrate mutations in those patients with post-ACTH ⁵-steroid precursor levels between 5 and 10 SD above the normal mean levels (181). Therefore, the hormonal levels for ACTH-stimulated 5-steroids in patients with a mild variant of 3ß-HSD deficiency are predicted to be higher than 10 SD above the normal mean value (169).

2. Idiopathic functional adrenal hyperandrogenism. Exaggerated androgenic precursor responses to ACTH testing were first reported in adult hyperandrogenic women (182) and subsequently found to be a common finding in hyperandrogenic adolescents and children with premature adrenarche (183, 184). Typically, these patients show prompt and prominent hyperresponsiveness to ACTH (not only more than 2 SD above the mean for normal age- and sex-matched controls but also above Tanner stage-matched controls) of the ⁵-steroids DHEA and 17-OH Preg, with 50% of them also showing an excessive response of androstenedione (185) and a concomitant hyperresponse of 17-OHP (182, 186). In this group of patients, the post-ACTH ratios of plasma 17-ketosteroids to cortisol have been found compatible with increased 17,20-lyase activity (186). This pattern of adrenal secretion resembles an exaggeration of adrenarche and has conservatively been considered "idiopathic," as it cannot be assigned to any well established pathophysiological entity, such as late-onset congenital adrenal hyperplasia. Thus, the entity has been described as functional adrenal hyperandrogenism (186).

Recently Banerjee et al. (187) reported that many prepubertal African-American and Caribbean Hispanic girls with premature adrenarche can have an androgen response to standard ACTH testing that is different from that which has been reported for the early pubertal stages. Approximately one-third of the 72 patients tested were found to have ACTH-stimulated levels of 17-OH Preg that were more than 2 SD above the mean for normal early pubertal children. In contrast, ACTH-stimulated levels of DHEA, androstenedione, and 17-OHP all remained in the early pubertal range.

Although the cause of idiopathic functional adrenal hyperandrogenism is unknown, it does not imply an enzymatic abnormality. It may simply represent hyperplasia of the zona reticularis (59). Another possibility is that it may be due to abnormal regulation or dysregulation of androgen formation by 17-hydroxylase and 17,20-lyase involving adrenal P450C17 activity, most prominently expressed in the ⁵-pathway (186). Furthermore, dysregulation of ovarian cytochrome P450C17, although most prominently involving the 4 pathway, often seems to coexist in a significant proportion of these patients, as discussed below (59, 186, 188).

F. Timing of puberty and final height
Previous analysis of small groups of patients has suggested that isolated premature adrenarche is not usually associated with a marked alteration in the timing of the child’s subsequent pubertal development (141, 147). Recent follow-up studies from two larger European population of girls with premature adrenarche and similar ethnic characteristics (70 Northern Italian and 57 Northern Spanish) have shown that advanced bone age and tall stature are frequently seen during the first years of follow-up and subsequently wane (157). Times of initiation of gonadarche (Tanner breast stage 2) at age 9.7 + 0.9 yr and menarche at 12.0 + 1.0 yr were comparable to maternal and population data (157) (Table 3). Furthermore, adult heights correlated well with height prognosis at time of diagnosis and at onset of puberty (Fig. 8). Final adult heights were generally above midparental heights, following the secular trend still present in both populations (157). Thus, premature adrenarche appears to cause a transient acceleration in growth and bone maturation with negligible effects on the onset and progression of puberty and final height (157, 189).

View larger version (35K): [in this window] [in a new window]   Figure 8. Relationship between height prognosis at diagnosis of premature adrenarche at onset of puberty and final height in 38 postpubertal girls, expressed in percentiles. Each three-dotted line represents an individual subject. Reprinted with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 74:254–257, 1992 (157 ). © The Endocrine Society.]

In a preliminary study we performed in a group of postpubertal girls with a history of premature adrenarche (193), 9 of 27 showed an increased score of hirsutism, using the Ferriman and Gallway scale (194) and elevated baseline androgen levels. Three of the girls also had oligomenorrhea and polycystic ovaries on ultrasound.

a. PCOS.
PCOS is the most common cause of hyperandrogenism in young females, with an incidence of approximately 3% in both adolescents and adults (59). Stein and Leventhal (195) were the first to define the association of polycystic ovaries and amenorrhea, and to recognize the high incidence of hirsutism and obesity in these patients (195). In its fully developed form, PCOS is characterized by menstrual abnormalities with anovulation, obesity, hyperandrogenemia, elevated plasma LH concentrations, and ultrasonographic evidence of polycystic ovaries (196, 197, 198). However, the subject remains controversial, in part due to the paucity of knowledge of its pathogenesis, and partly because endocrinological criteria for diagnosis are not well defined. Indeed, half of the women with the clinical syndrome lack the classic sonographic features of PCOS (199). Consequently, PCOS has come to be empirically defined on clinical grounds as chronic hyperandrogenic anovulation that is not secondary to underlying disease of the pituitary, ovaries, or adrenal glands (198, 200, 201).

GnRH agonists are potent and specific stimulators of the pituitary-gonadal axis. A single dose maximally stimulates gonadotropin secretion both in children and adults within 3–4 h and gonadal secretion within 18–24 h (202, 203, 204, 205, 206). It has proved to be a more effective stimulator of pituitary-gonadal function than a standard GnRH test (206). In adult women with well defined PCOS, the administration of the GnRH agonist nafarelin elicits pituitary-gonadal responses that are similar to those found in normal men and differ significantly from those elicited in normal women (204). This "masculinized" response is, according to Barnes et al. (204), characterized by an early increase in plasma LH levels 30–60 min after challenge and by androstenedione and a predominant 17-OHP hyperresponsiveness 16–24 h after GnRH agonist administration (204). This response pattern is unaffected by dexamethasone pretreatment (204). The secretory pattern seems to result from a generalized overactivity of steroidogenesis, which is particularly evident at the level of thecal 17-hydroxylase and 17,20-lyase activities of cytochrome P450C17 (199, 204). The exaggerated ovarian 17-OHP response does not appear to be mediated by increased secretion of LH in response to the agonist, as similar increases in 17-OHP can be elicited by the administration of a single and standardized (5000 IU, im) dose of human CG (hCG), both in normal and hyperandrogenic women (Fig. 9) (207). Therefore, it has been postulated that abnormal regulation of this androgen-forming enzyme within the ovary, rather than a steroidogenic block, underlies most PCOS cases (199).

View larger version (39K): [in this window] [in a new window]   Figure 9. Top, Baseline and peak 17-OHP responses to leuprolide acetate challenge (500 µg sc) in 16 oligomenorrheic premature adrenarche girls, 19 regularly-menstruating premature adrenache girls, and 12 age-matched controls. Values are mean ± SEM; a, P < 0.0001 vs. regularly menstruating patients and controls. [Modified with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 76:1599–1603, 1993 (209 ). © The Endocrine Society.] Bottom, Basal and peak 17-OHP levels in response to GnRH agonist leuprolide acetate (open bars) and hCG (filled bars) administration in PCOS women (right) and controls (left). *, Each 17-OHP value is significantly higher in PCOS subjects than in controls. [Modified with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 81:4103–4107, 1996 (207 ). © The Endocrine Society.]

We assessed the ovarian responses to challenge with the GnRH agonist leuprolide acetate in 35 adolescents with a history of premature adrenarche (age: 15.4 ± 1.5 yr) who were at least 3 yr beyond menarche (209). Sixteen of them showed hirsutism, oligomenorrhea, and elevated baseline testosterone and/or androstenedione levels. The remaining 19 were eumenorrheic, nonhirsute, and showed baseline androgen levels similar to those present in a group of 12 age- and BMI-matched controls. Subcutaneous administration of the agonist (500 µg) produced similar increases in gonadotropin levels in the three groups when tested at 6 h. However, 17-OHP and androstenedione levels 24 h after leuprolide acetate challenge were significantly higher in the oligomenorrheic girls than in the other two groups (Fig. 9). Specifically, only oligomenorrheic girls showed stimulated 17-OHP levels exceeding the mean ± 2 SD of the values found in controls (>160 ng/dl). The responses of the remaining androgens to the agonist were very similar among the three groups. In this cohort of 35 postpubertal girls with a history of premature adrenarche, almost half (45%) show a distinct response to GnRH agonist challenge, suggestive of functional ovarian hyperandrogenism, indicating the need for a continued postpubertal follow-up of these patients (209).

This pattern of ovarian steroidogenic response appears to be also particularly frequent in unselected hyperandrogenic women and adolescents (18, 185, 210). In our series, 58% of girls presenting with signs or symptoms of androgen excess showed abnormal 17-OHP responses to leuprolide acetate testing (183, 210). The sensitivity and specificity of the 17-OHP response to leuprolide acetate challenge in the diagnosis of functional ovarian hyperandrogenism compared with those after the dexamethasone suppression test, performed in the same patients, were 72.8% and 94.7%, respectively (183). Similar results have been reported in adult hyperandrogenic women after nafarelin testing, suggesting that the response of 17-OHP after GnRH agonist challenge can be used as a marker for the diagnosis of this type of ovarian dysfunction (183, 199).

c. Premature adrenarche and subsequent development of functional ovarian hyperandrogenism.
To identify possible biochemical markers for predicting the development of ovarian hyperandrogenism in girls with premature adrenarche, the relationship between adrenal androgen levels at premature adrenarche diagnosis and androgen responses to GnRH agonist challenge were examined. Baseline DHEAS and androstenedione levels at diagnosis of premature adrenarche correlated positively with 17-OHP values after leuprolide acetate challenge (Fig. 10), suggesting that functional ovarian hyperandrogenism is more frequent in those girls with pronounced premature adrenarche (209). Cytochrome P450C17 is encoded by the same gene in the adrenal and in the gonads, resulting in androgen synthesis in both glands (211). Thus, increased cytochrome P450C17 activity in both the adrenals and ovaries might first begin in the adrenal during childhood, causing premature adrenarche, and subsequently occur in the ovary, leading to signs and symptoms of functional ovarian hyperandrogenism.

View larger version (19K): [in this window] [in a new window]   Figure 10. Correlation between basal DHEAS and androstenedione (A) levels at diagnosis of premature adrenarche and 17-OHP values after GnRH agonist (leuprolide acetate) challenge. [Modified with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 76:1599–1603, 1993 (209 ). © The Endocrine Society.]

View larger version (35K): [in this window] [in a new window]   Figure 11. Incremental rises of 17-hydroxypregnenolone (17-Preg), DHEA, 17-OHP, and androstenedione (A) after GnRH agonist (leuprolide acetate) challenge in premature adrenarche girls and Tanner stage- and bone age-matched controls in early puberty (B2), midpuberty (B3), late puberty (B4), and postmenarche (B5). Values are the mean ± SEM. Note: postmenarcheal girls (i.e., B5) included in this study were specifically selected from among those who did not develop signs of hirsutism (31 B2 patients, age 9.8 ± 0.1 yr; 15 B3, age 11.0 ± 0.2 yr; 12 B4, age 12.0 ± 0.4 yr; 18 B5, age 15.4 ± 0.6 yr. Controls: 11 B2, age 11.2 ± 0.3 yr; 10 B3, age 13.1 ± 0.4 yr; 9 B5, age 15.7 ± 0.3 yr). Patients were matched for bone age. For details, see Ref. 213. [Reprinted with permission from L. Ibáñez et al.: Fertil Steril 67:849–855, 1997 (213 ).]

2. Adrenal function. Reevaluation of the adrenal function in postpubertal girls with a history of premature adrenarche has shown an increased incidence of idiopathic functional adrenal hyperandrogenism, i.e., DHEA, 17-OH Preg, and androstenedione hypersecretion in response to ACTH stimulation (182, 183). Fifty-five percent of the adolescent girls tested showed post-ACTH DHEA or 17-OH Preg and androstenedione levels greater than 2 SD beyond the mean for controls (215). All patients with idiopathic functional adrenal hyperandrogenism were hyperinsulinemic and in 70% of them, exaggerated 17-OHP responses to GnRH agonist stimulation suggestive of functional ovarian hyperandrogenism were also found (215). Overactivity of both adrenal 17,20-lyase and ovarian 17-hydroxylase/17,20-lyase coexist in the majority of cases of functional ovarian hyperandrogenism (186).

H. Patterns of insulin secretion
1. Insulin resistance at puberty. Puberty has been associated with increased fasting and glucose-stimulated insulin concentrations and a decrease in insulin sensitivity (216, 217, 218, 219). The insulin resistance during puberty is restricted to peripheral glucose metabolism and is associated with concomitant increases in GH, IGF-I, and IGF binding protein-3 (IGFBP-3) levels and a decrease in insulin-like growth factor binding protein-1 (IGFBP-1) and SHBG concentrations (216, 220, 221, 222, 223).

Differences in insulin sensitivity throughout puberty appear to be sex dependent (224) and also to show racial differences (225, 226). For example, African-American adolescents have lower insulin sensitivity and higher insulin levels during a hyperglycemic clamp than Tanner stage- and weight-matched Caucasian adolescents (225).

2. Hyperinsulinemia and premature adrenarche.
a. Prepubertal period.
The hyperinsulinemia and increased IGF-I activity during puberty have been proposed as inducing factors in the development of PCOS (212). Both insulin and IGF-I are capable of stimulating androgen production by ovarian thecal-interstitial cells and to augment the steroidogenesis and ACTH responsiveness of human adrenocortical cells in culture (121, 227, 228). However, whether hyperinsulinemia and insulin resistance may be primary in the development of ovarian hyperandrogenism is still unclear (229).

Oppenheimer et al. (230) were the first to relate ACTH-stimulated steroid hormone data to insulin sensitivity obtained from the frequent sampling intravenous glucose tolerance test (FSIVGTT) (231, 232) in 21 prepubertal African-American and Hispanic girls with premature adrenarche. Eleven girls had normal insulin sensitivity and 10 girls had an insulin sensitivity more than 2 SD below the mean of normal prepubertal girls. Insulin sensitivity correlated inversely with the ACTH-stimulated levels of 17-OH Preg and the ratio of 17-OH Preg/17-OHP. IGFBP-3 levels were normal and IGFBP-1 levels were low normal.

Just as in many women with PCOS, the hyperandrogenism of prepubertal African-American and Caribbean Hispanic girls with premature adrenarche can be associated with hyperinsulinism. The increased insulin levels may result in decreased levels of IGFBP-1, which in turn, can increase the availability of IGF-I (233). IGF-I, together with insulin, may directly stimulate ovarian steroidogenesis (227, 233). In carefully conducted in vitro studies IGF-I and insulin synergize with LH to stimulate androgen production by normal ovarian theca-interstitial cells (228). More recent data from our group suggest a primary role of altered insulin sensitivity and IGFBP-1 activity as hyperandrogenism develops (234, 235).

Hyperinsulinemia after an oral glucose load is a common feature in lean premature adrenarche girls before and also during pubertal development (236) (Fig. 12). The hyperinsulinism is associated with an increased initial insulin response to glucose and a later rise in insulin sensitivity compared with bone age- and Tanner stage-matched girls used as controls. These patients also show increased free androgen indexes and lower serum SHBG and IGFBP-1 levels at most pubertal stages tested (236).

View larger version (30K): [in this window] [in a new window]   Figure 12. Mean serum insulin (MSI) in premature adrenarche girls and in Tanner stage-matched controls. Values are mean ± SEM. *, Significantly different from controls. P < 0.03, P = 0.03, P = 0.03, and P < 0.05 for B1, B2, B3, and B5, respectively. [Reprinted with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 82:2283–2288, 1997 (236 ). © The Endocrine Society.]

More recently we documented the utility of fasting glucose insulin ratios as a simple measure evaluating insulin resistance in girls with premature adrenarche (242A 242B ).

b. Postpubertal period.
Hyperinsulinism and insulin resistance have been consistently reported in obese and lean women with functional ovarian hyperandrogenism (243), PCOS patients (244, 245, 246, 247, 248, 249, 250, 251, 252), and hyperandrogenic adolescents (210), although some reports have failed to find a linear relationship between hyperinsulinemia and hyperandrogenism in hirsute patients (253). PCOS women may already have impaired glucose tolerance (IGT) or frank type 2 diabetes by their third decade (244, 245, 254). Although PCOS and obesity have a synergistic deleterious effect on glucose homeostasis (244), insulin resistance has also been reported in lean PCOS patients (245, 246, 247, 251) and appears to be directly related to the degree of hyperandrogenism (246, 247).

Ethnicity has been proven to be an independent risk factor for insulin resistance development in PCOS women (255, 256, 257). For example, Caribbean-Hispanic PCOS women are significantly more insulin resistant than non-Hispanic women matched for age, weight, and body composition (255).

The mechanisms of insulin resistance in PCOS are still unclear (258). Although it has been hypothesized that androgens directly decrease insulin action (259, 260), studies in which the hormonal environment has been manipulated have yielded conflicting results. Suppression of androgen action with antiandrogenic drugs in hyperandrogenic women has been shown to either have no effect on insulin levels or result in significant improvement in insulin sensitivity (261, 262, 263, 264). On the other hand, it has been proposed that hyperinsulinemia per se causes hyperandrogenism (259, 265). Consistent with this hypothesis, in short-term studies of women with PCOS, insulin infusions have been shown to increase androgen levels, whereas lowering circulating insulin levels with diazoxide, troglitazone, or a somatostatin analog has also decreased androgen levels (266, 267, 268, 269). The report of Nestler and Jakubowicz (270) that hyperinsulinemia stimulates ovarian P450C17 activity in obese PCOS women suggests that, at least in some subsets of hyperandrogenic patients, hyperinsulinemia and dysregulation of ovarian androgen secretion are pathogenetically linked (270, 271). Postpubertal girls with a history of premature adrenarche and functional ovarian hyperandrogenism demonstrate more hyperinsulinism than normal adolescents after an oral glucose load (272). Furthermore, 27% of our cohort of postpubertal premature adrenarche girls without ovarian androgen excess also show mean serum insulin values well above the upper normal limit for controls. The hyperinsulinemia is directly related to the degree of ovarian hyperandrogenism (assessed by an abnormal 17-OHP response to GnRH agonist challenge) in functional ovarian hyperandrogenism patients and to the free androgen index (equivalent to free testosterone) levels in both girls with ovarian hyperandrogenism and subjects without ovarian hyperandrogenism (272) (Fig. 13).

View larger version (16K): [in this window] [in a new window]   Figure 13. Relationship between mean serum insulin (MSI) levels and the free androgen indexes (FAI) in postpubertal premature adrenarche girls with functional ovarian hyperandrogenism (FOH), premature adrenarche girls without functional ovarian hyperandrogenism (non-FOH), and controls. [Modified with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 81:1237–1243, 1996 (272 ). © The Endocrine Society.]

c. Type 2 diabetes mellitus and adrenal/ovarian hyperandrogenism: a familial syndrome?
Type 2 diabetes mellitus and/or hirsutism with or without polycystic ovaries have been described in kindreds of probands with PCOS (273). However, these association studies may be weakened by the heterogeneity of the syndrome, and by the diverse etiologies of these phenotypic characteristics. Consequently, homogenous populations are needed for identifying biochemical intermediary phenotypes that are fixed defects in PCOS and functional ovarian hyperandrogenism and may be present in family members.

Preliminary studies performed by us suggested that the search for biochemical intermediary phenotypes may begin with a homogeneous population in which probands meet four strict criteria: premature adrenarche, clinical evidence of hyperandrogenism, exaggerated 17-OHP responses to GnRH agonist challenge suggestive of functional ovarian hyperandrogenism, and hyperinsulinemia. The study of 60 first-degree relatives belonging to nine families with two affected adolescents each has shown an increased prevalence of both type 2 diabetes mellitus and IGT compared with our normal age- and BMI-matched population (type 2 diabetes mellitus, 22.2% vs. 1.5%; IGT, 27.7% vs. 8.2%) (274).

Even more striking findings with regard to the prevalence of type 2 diabetes mellitus were obtained among first-degree relatives of a group consisting of African-American and Caribbean-Hispanic patients with premature adrenarche (235). In this study 25 of 35 children studied had at least one first- or second-degree relative with type 2 diabetes mellitus. Female first-degree relatives also had lower serum SHBG levels compared with age-matched population controls, possibly secondary to their hyperinsulinemia (274).

I. Lipid levels in premature menarche
Considerable epidemiological controversy exists as to whether hyperinsulinemia, both fasting and postprandial, is an independent risk factor for the development of cardiovascular disease (275, 276, 277). Preliminary data of the lipid patterns in premature adrenarche girls show that hyperinsulinemia is accompanied by increased triglyceride levels compared with a Tanner stage- and age-matched population (278) (Fig. 14) and support the proposal that the genesis of an atherogenic pattern of risk factors may start in childhood (279, 280). Insulin appears to be a major determinant of their lipid status with no additional effects of androgens or estrogens on serum lipid levels.

View larger version (17K): [in this window] [in a new window]   Figure 14. Serum triglyceride levels in premature adrenarche patients and controls throughout all stages of pubertal development. B1 to B5, Tanner breast stages 1 to 5. ap = 0.01; bp = 0.006, and cp = 0.001 vs. controls. [Modified with permission from L. Ibáñez et al.: Diabetologia 41:1057–1063, 1998 (278 ).]

View larger version (27K): [in this window] [in a new window]   Figure 15. Acanthosis nigricans affecting the neck of an 8-yr-old subject with premature adrenarche and insulin resistance from study described in Ref. 230.

It is well known that adults with acanthosis nigricans are at risk for having the long-term complications of hyperinsulinism, including type 2 diabetes, hypertension, lipid abnormalities, and atherosclerosis (289). However, information regarding the frequency and significance of acanthosis nigricans in children is sparse. According to surveys including large populations, acanthosis nigricans can be detected in 7.1% of school-age children (285). Although seen predominantly in obese children, acanthosis nigricans also occurs in healthy nonobese children. A positive correlation between severity of acanthosis nigricans and fasting serum insulin levels was observed (285), although no correlation was found with hyperandrogenism. Oppenheimer et al. (230) reported an increased incidence of acanthosis nigricans among their population of Black and Hispanic girls with premature adrenarche; in the prepubertal period, these girls already showed a decrease in insulin sensitivity. Whether these children are destined to have the same metabolic complications as adults with acanthosis nigricans is not known. It is possible that improvement of insulin sensitivity with metformin or troglitazone (269, 270) might also improve acanthosis nigricans.

K. Future avenues of investigation
1. Hyperinsulinemia and premature adrenarche: a common pathogenetic link? The finding of increased insulin levels in prepubertal girls with premature adrenarche suggests that hyperinsulinemia and premature adrenarche might have a common pathogenetic mechanism (230, 235, 236, 290). Similarly, Dunaif et al. (291) reported that increased insulin receptor serine phosphorylation decreases its protein kinase activity and is one likely mechanism for the postbinding defect in insulin action characteristic of PCOS. Defects producing insulin resistance in PCOS appear to involve the early steps of insulin receptor-mediated signaling and are associated with increased serine phosphorylation of the insulin receptor (255). Abnormal activation of this process might simultaneously increase the serine phosphorylation of ovarian and adrenal cytochrome P450C17 causing functional ovarian and adrenal hyperandrogenism, and the serine phosphorylation of the insulin receptor causing hyperinsulinemia and insulin resistance, thus providing a common pathway for the three principal features of some forms of hyperandrogenism.

Insulin and the IGF system seem to modulate steroid metabolism in diverse sites, as well as serving as generalized regulators of diverse cell biology systems (120, 227, 228, 292, 293, 294). Insulin and IGF-I are approximately equal in potency in the ovary, and recent evidence suggests that insulin effects there in PCOS are mediated through an insulin receptor (293, 295). In hyperandrogenic women, hyperinsulinemia, within the high physiological range, may similarly affect the regulation of adrenal steroidogenesis by potentiating both ACTH-stimulated 17-hydroxylase and 17,20-lyase activities (296). Therefore, although the hyperinsulinism present in premature adrenarche patients is usually moderate, it may precipitate hyperandrogenemia in vulnerable individuals by acting as a "second hit" to unmask latent abnormalities in the regulation of adrenal and ovarian androgen secretion.

2. Genetic factors in ovarian hyperandrogenism. The relative importance of genetic and environmental factors in the etiology of ovarian hyperandrogenism and, specifically, in PCOS, remains unclear. The search of the gene or genes responsible has been hindered by the heterogeneity of populations of women with PCOS, and by the problems that confound its clinical characterization (297, 298).

Familial studies have indicated variously: autosomal dominance (298, 299, 300), segregation ratios exceeding autosomal dominance (301), or have emphasized the relative importance of environmental factors in the genesis of this disorder (302). The autosomal mode of inheritance of PCOS has been emphasized by the finding of a high prevalence of polycystic ovaries and premature male balding in relatives of affected individuals (303).

Cytochrome P450C17, the rate-limiting step in androgen biosynthesis in the ovaries and the adrenals was regarded as a good candidate for involvement in the etiology of PCOS (300). The analysis of the CYP17 gene, coding for P450C17 in PCOS/male pattern baldness pedigrees, identified a base pair change in the CYP17 promoter region conferring an additional SP1-type promoter element (304). Preliminary studies of the frequency of this variant (A2) PCOS allele in a small, case-controlled data set seemed to indicate an association of the A2 allele with PCOS (304). However, more extended studies have revealed that this gene does not play a major role in the etiology of hyperandrogenemia and that the base pair change identified in the promoter region of the CYP17 gene is a common polymorphism (305).

Recently, Waterworth et al. (306) provided evidence for linkage of familial PCOS to the variable number of tandem-repeat loci upstream of the insulin gene, which regulates insulin expression (307, 308). A strong allelic association of a pentanucleotide repeat polymorphism on the promoter region of the CYP11A, the gene encoding cytochrome P450_scc, has also been described in an additional group of hyperandrogenic patients (309). Heterozygosity for mutations in the CYP21 gene does not appear to increase the risk of hyperandrogenism (310).

In a recent elegant paper Urbanek et al. (311) analyzed genetic linkage and population association for a set of 37 candidate genes for PCOS and hyperandrogenism. The strongest evidence for linkage was with the follistatin gene. Only the linkage with follistatin remains significant after correction for multiple testing. Follistatin, an activin-binding protein, metabolizes the biological activities of activin in vitro and in vivo. Activin, a member of the transforming growth factor ß superfamily, and follistatin are expressed in numerous tissues, including ovary, pituitary, adrenal cortex, and pancreas. An increase in level or in functional activity of follistatin might therefore increase ovarian androgen production, reduce FSH levels, and impair insulin release. These changes are all more or less characteristic features of PCOS. These data, which do require confirmation, suggest therefore that variation at or near the follistatin gene contributes to hyperandrogenism seen in PCOS.

L. Premature adrenarche, hyperinsulinism, and ovarian dysfunction: possible relation to reduced fetal growth
Intrauterine growth retardation (IUGR) is known to be associated with hypoplasia and even atrophy of the fetal zone at birth (312). DHEAS concentrations are significantly lower in the first 24 h of life in infants of 37–40 weeks’ gestation with IUGR compared with children appropriate in gestational age and in weight and of the same postnatal ages (313). This is consistent with low urinary 16ßOH DHEAS in growth-retarded newborn infants (314). These findings suggest, but do not prove, that the fetal zone of the neonatal adrenal cortex is a major source of circulating DHEAS in the newborn period (313).

Barker et al. (315, 316) reported increased rates of cardiovascular disease and type 2 diabetes mellitus in adults born with IUGR. According to Barker’s concept, the growth-retarded fetus adapts to undernutrition and survives by altering endocrine and metabolic set points that appear to remain altered postnatally. Recent data suggest that fetal growth may also be a modulator of adrenarche: in pairs of discordant siblings, one of which had IUGR while the other had an appropriate birth weight, DHEAS, when measured at a median age of 8.2 yr, was on average twice as high (range 1.1- to 7-fold) in the former IUGR child who had "caught up" as in the sibling of appropriate birth weight. The children who had not shown catch-up growth still had subnormal DHEAS levels for age (317). These findings identify a tentative link between the advent of adrenarche and factors controlling fetal growth. This finding further supports the concept of early endocrine "programming" and extends this principle to adrenarche (317).

More recently, we found that premature adrenarche, hyperinsulinism, low IGFBP-1, dyslipemia, anovulation, and hyperandrogenism in girls, as well as their combinations, have each been related to reduced fetal growth, indicating that these constellations may indeed have a prenatal origin (318, 319, 320, 321, 322) The average degree of prenatal growth restriction is more pronounced in those girls presenting with a constellation of these abnormalities, i.e., premature pubarche, ovarian hyperandrogenism, and hyperinsulinism (Fig. 16). The precise mechanisms governing these relationships are currently unknown.

View larger version (12K): [in this window] [in a new window]   Figure 16. Birth weight scores of postmenarcheal control girls and postmenarcheal girls with a history of precocious adrenarche. [Reproduced with permission from L. Ibáñez et al.: J Clin Endocrinol Metab 83:3558–3662, 1998 (318 ). © The Endocrine Society.]

	III. Conclusions

Top Abstract I. Adrenarche II. Premature Adrenarche III. Conclusions References

 
Adrenarche is the "puberty" of the adrenal gland. The descriptive clinical term pubarche describes the appearance of pubic hair. Adrenarche occurs only in humans and higher primates. Adrenarche is characterized by a profound change in the degree and in the pattern of the adrenal secretory response to ACTH. Levels of 17-OH Preg, DHEA, and DHEA-S increase strikingly.

Mechanisms for initiation of adrenal androgen secretion at adrenarche are still not well understood. Maturational increases in 17-hydroxylase and 17,20-lyase are seen together with a low activity of 3ß-HSD. There is good evidence that the zona reticularis is the source of adrenal androgens. Adrenarche and gonadarche are regulated differently.

Premature adrenarche has no adverse effects on the onset and progression of gonadarche and final height. Premature pubarche driven by premature adrenarche in girls is, in contrast to boys, not necessarily just a normal maturational process occurring early. ACTH stimulation testing should be reserved for atypical premature adrenarche, and the criteria for the diagnosis of steroidogenic enzyme deficiencies should be stringent. Many girls with premature adrenarche show not only hyperinsulinemia already in the prepubertal period but also an increased incidence of ovulatory dysfunction, functional ovarian hyperandrogenism, dyslipidemia, and obesity at adolescence, indicating long-term follow-up of these patients into adulthood. The possible causal role of hyperinsulinemia on adrenal and/or ovarian hypersecretion of androgens in premature adrenarche girls, the association of these endocrine-metabolic abnormalities with reduced fetal growth, and their genetic basis remain to be elucidated.

In the absence of controlled longitudinal studies, the cross-sectional data available from our studies suggest that premature pubarche driven by premature adrenarche and hyperinsulinemia may precede the development of ovarian hyperandrogenism, and this sequence may have an early origin with low birth weight serving as a marker. Premature adrenarche may thus be a forerunner of syndrome X in some girls.

	Acknowledgments

 
We wish to acknowledge the excellent secretarial work of Ms. Lorraine Miller and Ms. Elizabeth Kitzinger.

	Footnotes

 
Address reprint requests to: Paul Saenger, M.D., Division of Pediatric Endocrinology, Albert Einstein College of Medicine/Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. E-mail: PHSAENGER{at}AOL.COM

¹ Supported in part by the Genentech Foundation for Growth and Development and by Grant 95/5357 from the Fondo de Investigaciones de la Seguridad Social, National Health Service (Madrid, Spain).

	References

Top Abstract I. Adrenarche II. Premature Adrenarche III. Conclusions References

 

1. Talbot NB, Butler AM, Berman RA, Rodriguez PM, MacLachan EA 1943 Excretion of 17-ketosteroids by normal and by abnormal children. Am J Dis Child 65:364–375[Abstract/Free Full Text]
2. Albright F, Smith PH, Fraser R 1942 A syndrome characterized by primary ovarian insufficiency and decreased stature. Report of 11 cases with digression on hormonal control of axillary and pubic hair. Am J Med Sci 204:625–648[CrossRef]
3. Albright F 1947 Osteoporosis. Ann Intern Med 27:861–882[Abstract/Free Full Text]
4. Reiter E, Saenger P 1997 Premature adrenarche. The Endocrinologist 7:85–88
5. Goldstein S, Saenger P 1984 The physiology of puberty. In: Moss AJ (ed) Pediatrics Update: Reviews for Physicians. Elsevier, New York, pp 63–93
6. Silverman SH, Migeon CJ, Rosenberg E, Wilkins L 1952 Precocious growth of sexual hair without other secondary sexual development: "premature pubarche," a constitutional variation of adolescence. Pediatrics 10:426–432[Abstract/Free Full Text]
7. Hamburger C 1948 Normal urinary excretion of neutral 17-ketosteroids with special reference to age and sex variations. Acta Endocrinol (Copenh) 1:19–37[Abstract/Free Full Text]
8. Mills IH, Brooks RV, Prunty FTG 1962 The relationship between the production of cortisol and of androgen by the human adrenal. In: Currie AR, Symington T, Grant JK (eds) The Human Adrenal Cortex. Livingstone, London, pp 20–29
9. Migeon CJ, Plager JE 1954 Identification and isolation of dehydroepiandrosterone from peripheral human plasma. J Biol Chem 209:767–772[Free Full Text]
10. Migeon CJ 1956 Identification and isolation of androsterone from peripheral human plasma. J Biol Chem 218:941–949[Free Full Text]
11. Migeon CJ, Keller AR, Lawrence B, Shepard TH 1957 Dehydroepiandrosterone and androsterone levels in human plasma: effect of age and sex, day to day and diurnal variations. J Clin Endocrinol Metab 17:1056–1062
12. Rosenfield RL, Eberlein WR 1969 Plasma 17-ketosteroid levels during adolescence. J Pediatr 74:932–936[CrossRef][Medline]
13. Baulieu EE, Corpechot C, Dray F, Emiliozzi R, Lebeau MC, Mauvais-Jarvis P, Robel P 1965 An adrenal secreted androgen: dehydroisoandrosterone sulfate: its metabolism and a tentative generalization on the metabolism of other steroid conjugates in man. Recent Prog Horm Res 21:411–500
14. Hornsby PJ 1997 DHEA: a biologist’s perspective. J Am Geriatr Soc 45:1395–1401[Medline]
15. Holownia P, Owen EJ, Conway GS, Round J, Honour JW 1992 Studies to confirm the source of 11-hydroxyandrostenedione. J Steroid Biochem Mol Biol 41:875–880[CrossRef][Medline]
16. Grumbach MM, Richards GE, Conte FA, Kaplan SL 1978 Clinical disorders of adrenal function and puberty: an assessment of the role of the adrenal cortex in normal and abnormal puberty in man and evidence for an ACTH-like pituitary adrenal androgen stimulation hormone. In: James VHT, Serio M, Giusti G, Martini L (eds) The Endocrine Function of the Human Adrenal Cortex. Serono Symposia 18. Academic Press, London, pp 583–612
17. Sklar CA, Kaplan SL, Grumbach MM 1980 Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and consti-tutionally delayed growth and adolescence. J Clin Endocrinol Metab 51:548–556[Abstract/Free Full Text]
18. Apter D, Pakkerinen A, Hammond GL, Vihko R 1979 Adrenocortical function and puberty, serum ACTH, cortisol and dehydroepiandrosterone in girls and boys. Acta Pediatr Scand 69:599–606
19. Kenny FM, Preeyasombat C, Migeon CJ 1966 Cortisol production rate: normal infants, children and adults. Pediatrics 37:34–42[Abstract/Free Full Text]
20. Lashansky G, Saenger P, Fishman K, Gautier T, Mayes D, Berg G, DiMartino-Nardi J, Reiter E 1991 Normative data for adrenal steroidogenesis in a healthy pediatric population: age and sex-related changes after ACTH stimulation. J Clin Endocrinol Metab 73:674–686[Abstract/Free Full Text]
21. Lashansky G, Saenger P, DiMartino-Nardi J, Gautier T, Mayes D, Berg G, Reiter E 1992 Normative data for the steroidogenic response of mineralocorticoids and their precursors to adrenocorticotropin in a healthy pediatric population. J Clin Endocrinol Metab 75:1491–1496[Abstract]
22. Oberfield SE, Mayes DM, Levine LS 1990 Adrenal steroidogenic function in black and Hispanic population with precocious pubarche. J Clin Endocrinol Metab 70:76–82[Abstract/Free Full Text]
23. Oberfield SE, Amer T, Tyson D, Soranno D, David R, Lee E, Levine LS 1994 Altered sensitivity to low dose dexamethasone in a subset of patients with premature adrenarche. J Clin Endocrinol Metab 79:1102–1104[Abstract]
24. Dewailly D, Vantyghem MC, Lemaire C, Dufosse F, Racadot A, Fossati P 1988 Screening heterozygotes for 21-hydroxylase deficiency among hirsute women: lack of utility of the adrenocorticotropin hormone test. Fertil Steril 50:228–232[Medline]
25. Forest ME, Saez JM, Bertrand J 1975 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, pp 339–366
26. Korth-Schutz S, Levine LS, New MI 1976 Serum androgens in normal prepubertal and pubertal children with precocious adrenarche. J Clin Endocrinol Metab 42:117–124[Abstract/Free Full Text]
27. Korth-Schutz S, Levine LS, New MI 1976 Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion. J Clin Endocrinol Metab 42:1005–1013[Abstract/Free Full Text]
28. Hopper BR, Yen SCC 1975 Circulating concentrations of dehydro-epiandrosterone and dehydroepiandrosterone sulfate during puberty. J Clin Endocrinol Metab 40:458–461[Abstract/Free Full Text]
29. DePerretti E, Forest MG 1986 Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in humans: the use of a sensitive radioimmunoassay. J Clin Endocrinol Metab 43:982–991[Abstract/Free Full Text]
30. Reiter E, Fuldauer VG, Root AW 1977 Secretion of the adrenal androgen, dehydroepiandrosterone sulfate during normal infancy, childhood and adolescence, in sick infants and in children with endocrinologic abnormalities. J Pediatr 90:766–770[CrossRef][Medline]
31. Forest MG 1978 Age-related response to plasma testosterone, 4- androstenedione, and cortisol to adrenocorticopin in infants, children and adults. J Clin Endocrinol Metab 47:931–937[Abstract/Free Full Text]
32. DePerretti E, Forest MG 1978 Pattern of plasma dehydroepiandrosterone sulfate levels in humans from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab 47:572–577[Abstract/Free Full Text]
33. Korth-Schutz S, Levine LS, New MI 1976 Evidence for the adrenal source of androgens in precocious adrenarche. Acta Endocrinol (Copenh) 82:342–352[Abstract/Free Full Text]
34. Kelnar CJH, Brook CGD 1983 A mixed longitudinal study of adrenal steroid excretion in childhood and a mechanism of adrenarche. Clin Endocrinol (Oxf) 19:117–129[Medline]
35. Wierman ME, Beardsworth DE, Crawford JD, Crigler Jr JF, Mansfield J, Bode HM, Boepple PA, Kushner DC, Crowley Jr WF 1986 Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche. J Clin Invest 77:121–126
36. Parker LN, Odell W 1980 Control of adrenal androgen secretion. Endocr Rev 1:392–410[Abstract/Free Full Text]
37. Parker LN 1991 Control of adrenal androgen secretion. Endocrinol Metab Clin North Am 20:401–421[Medline]
38. Parker LN 1991 Adrenarche. Endocrinol Metab Clin North Am 20:71–83[Medline]
39. Endoh A, Kristiansen SB, Carson PR, Buster JE, Hornsby PJ 1996 The zona reticularis is the site of biosynthesis of DHEA and DHEAS in the adult human adrenal cortex. J Clin Endocrinol Metab 81:3558–3565[Abstract]
40. Lanman JT 1953 The fetal zone of the adrenal gland. Medicine (Baltimore) 32:389–430[Medline]
41. Blackman Jr SS 1946 Concerning function and origin of reticular zone of the adrenal cortex: hyperplasia in adrenogenital syndrome. Bull Johns Hopkins Hosp 78:180–217
42. Babalola AA, Ellis G 1985 Serum DHEAS in a normal pediatric population. Clin Biochem 18:184–189[CrossRef][Medline]
43. Pepe GJ, Albrecht ED 1990 Regulation of the primate fetal adrenal cortex. Endocr Rev 11:151–176[Abstract/Free Full Text]
44. Mesiano S, Jaffe RB 1997 Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev 18:378–403[Abstract/Free Full Text]
45. Zemel BS, Katz SH 1986 The contribution of adrenal and gonadal androgens to the growth in height of adolescent males. Am J Phys Anthropol 71:459–466[CrossRef][Medline]
46. Largo RH 1993 Catch-up growth during adolescence. Horm Res 39 [Suppl]:41- 48
47. Karlberg J, Engstrom I, Karlberg P, Fryer JG 1987 Analyses of linear growth using a mathematical model. Acta Paediatr Scand [Suppl] 76:478–488
48. Cohen H, Hay ID, Bistall GH, Thomson JA 1982 Failure of adrenal androgens to induce puberty in familial cytomegalic adrenocortical hypoplasia. Lancet 2:1471–1472
49. Maruyama Y, Aoki N, Suzuki Y, Ohno Y, Imamura M, Saika T, Sinohara H, Yamamoto T 1987 SBP Sex-steroid-binding plasma protein, testosterone, oestradiol and DHEA in prepuberty and puberty. Acta Endocrinol (Copenh) 114:60–66[Abstract/Free Full Text]
50. Rosenfield RL, Fang VS, Dupon C, Kim MH, Refetoff S 1973 The effects of low doses of depot estradiol and testosterone in teenagers with ovarian failure and Turner’s syndrome. J Clin Endocrinol Metab 37:574–580[Abstract/Free Full Text]
51. Heinrichs WL, Tabei T, Kuwabara Y, Burry K, Resko J, Petra P, Shiller H, Namkung P 1979 Differentiation and regulation of peripheral androgen metabolism in rats and rhesus monkeys. Am J Obstet Gynecol 135:974–982[Medline]
52. Cutler GB, Loriaux DL 1980 Adrenarche and its relationship to the onset of puberty. Fed Proc 39:2384–2392[Medline]
53. Cutler Jr GB, Glenn M, Bush M, Hodgen GD, Graham CE, Loriaux DL 1978 Adrenarche: a study of rodents, domestic animals and primates. Endocrinology 103:2112–2118[Abstract/Free Full Text]
54. Smail PJ, Faiman C, Hobson WC, Fuller GB, Winter JSD 1982 Further studies on adrenarche in non-human primates. Endocrinology 111:844–848[Abstract/Free Full Text]
55. Meusy-Dessolle N, Dang PC 1985 Plasma concentrations of testosterone, dihydrotestosterone, 4-androstenedione, dehydroepiandrosterone and oestradiol-17 in the crab-eating monkey (Macaca fascicularis) from birth to adulthood. J Reprod Fertil 74:347–359[Abstract/Free Full Text]
56. Lane MA, Ingram DK, Ball SS, Roth GS 1997 Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction. J Clin Endocrinol Metab 82:2093–2096[Abstract/Free Full Text]
57. Hornsby PJ 1998 The biosynthesis of DHEA by the adrenal cortex and its age-related decline. In: Watson RW (ed) DHEA: Health Promotion and Aging. Academic, Harwood, NJ, pp 1–13
58. Miller WL, Tyrell JB 1995 The adrenal cortex. In: Felig P, Baxter JD, Frohman LA (eds) Endocrinology and Metabolism, ed. 3. McGraw-Hill, New York, pp 555–711
59. Rosenfield RL, Lucky AW 1993 Acne, hirsutism, and alopecia in adolescent girls. Endocrinol Metab Clin North Am 22:507–532[Medline]
60. Hyatt PJ, Bhatt K, Tait JF 1983 Steroid biosynthesis by zona fasciculata and zona reticularis cells purified from the mammalian adrenal cortex. J Steroid Biochem 19:953–959[CrossRef][Medline]
61. Jones T, Browney BG, Cowley TH, Griffiths K 1974 Ultramicrochemical and tissue culture studies of adrenal tissue. In: Jacoby F, Rojan KT (eds) Tissue Culture in Medical Research. Heinemann, London, pp 263–272
62. Neville AM, O’Hare MC 1982 The human adrenal cortex, pathology and biology: an integrated approach. Springer Verlag, Berlin
63. O’Hare MJ, Nice EC 1980 Regulation of androgen secretion and sulfoconjugation in the adult human adrenal cortex: studies with primary monolayer cell cultures. In: Genazzani AR, Thijssen JHH, Siiteri PK (eds) Adrenal Androgens. Raven, New York, pp 7–25
64. Zhang LH, Rodriguez H, Ohno S, Miller WL 1995 Serine phosphorylation of human P450C17 increases 17,20 lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA 92:10619–10623[Abstract/Free Full Text]
65. Kennerson AR, McDonald DA, Adams JB 1983 Dehydroepiandrosterone sulfotransferase localization in human adrenal glands: a light and electron microscopic study. J Clin Endocrinol Metab 56:786–790[Abstract/Free Full Text]
66. Dickerman Z, Gant DR, Faiman C, Winter JSD 1984 Intraadrenal steroid concentration in man: zonal differences and developmental changes. J Clin Endocrinol Metab 59:1031–1036[Abstract/Free Full Text]
67. Meikle AW, Daynes RA, Araneo BA 1991 Adrenal androgen secretion and biologic effects. Endocrinol Metab Clin North Am 20:381–400[Medline]
68. Cameron EHD, Jones T, Jones D, Anderson ABM, Griffiths K 1969 Further studies on the relationship between C19 and C21 steroid synthesis in the human adrenal gland. J Endocrinol 45:215–230[Abstract/Free Full Text]
69. Lieberman S, Prasad VVK 1990 Heterodox notions on pathways of steroidogenesis. Endocr Rev 11:469–493[Abstract/Free Full Text]
70. Rosenfeld R, Hellman L, Roffwarg H, Weitzman ED, Fukushima DK, Gallagher T 1971 Dehydroisoandrosterone is secreted episodically and synchronously with cortisol by normal man. J Clin Endocrinol Metab 33:87–92[Abstract/Free Full Text]
71. Rotter J, Wong F, Lifrak ET, Parker LN 1985 A genetic component to the variation of dehydroepiandrosterone sulfate. Metabolism 34:731–736[CrossRef][Medline]
72. Akamine Y, Kato K, Ibayashi H 1980 Studies on changes in the concentration of serum adrenal androgens in pubertal twins. Acta Endocrinol (Copenh) 93:356–364[Abstract/Free Full Text]
73. Dhom G 1973 The prepubertal and pubertal growth of the adrenal (adrenarche). Beitr Pathol 150:357–377[Medline]
74. Parker LN, Gral T, Perrigo V, Skowsky R 1981 Decreased adrenal androgen sensitivity to ACTH during aging. Metab Clin Exp 30:601–604
75. Meldrum D, Davidson B, Tataryn IV, Judd HL 1981 Changes in circulating steroids with aging in postmenopausal women. Obstet Gynecol 57:624–628[Medline]
76. Orentreich N, Brind JL, Rizer RL, Vogelman JH 1984 Age changes and sex difference in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59:551–555[Abstract/Free Full Text]
77. Thomas G, Frenoy N, Legrain S, Sebag-Lanoe R, Baulieu EE, Debuire B 1994 Serum dehydroepiandrosterone sulfate levels as an individual marker. J Clin Endocrinol Metab 79:1273–1276[Abstract]
78. Kreiner E, Dhom G 1979 Altersveraenderungen der menschlichen Neben-niere. Zentralbl Allg Pathol Anat 23:351–356
79. Warne GL, Carter JM, Faiman C, Reyes Fl Winter JSD 1978 Hormonal changes in girls with precocious adrenarche: a possible role for estradiol or prolactin. J Pediatr 92:743–747[CrossRef][Medline]
80. Wathen NC, Hodgkinson S, Charid T 1985 The relationship between prolactin, DHEAS and testosterone in normally menstruating females. Acta Endocrinol (Copenh) 109:173–175[Abstract/Free Full Text]
81. Sklar CA, Kaplan SL, Grumbach MM 1981 Lack of effect of estrogens on adrenal androgen secretion in children and adolescents with a comment on oestrogens and pubic hair growth. Clin Endocrinol (Oxf) 14:311–320[Medline]
82. Zachmann M, Manella B, Eiholzer U, Bucher H, Prader A 1984 Influence of estrogen in high and low doses on plasma steroid concentrations in girls with tall stature and Turner’s syndrome. Acta Endocrinol (Copenh)106:368–373
83. Sobrinho LG, Kase NG, Grunt JA 1971 Changes in adrenocortical function of patients with gonadal dysgenesis after treatment with estrogen. J Clin Endocrinol Metab 33:110–114[Abstract/Free Full Text]
84. Mattila AL, Perheentupa J, Personen K, Viinikka K 1985 Epidermal growth factor in human urine from birth to puberty. J Clin Endocrinol Metab 61:997–1000[Abstract/Free Full Text]
85. Keymolen V, Dor P, Borkowski A 1976 Output of estrogens, testosterone and their precursors by isolated human adrenal cells as compared with that of glucocorticosteroids. J Endocrinol 71:219–229[Abstract/Free Full Text]
86. Parker LN, Lifrak E, Kawahara CK, Geduld SI, Kozbur XM 1983 Angiotensin II potentiates ACTH-stimulated adrenal androgen secretion. J Steroid Biochem 18:205–208[CrossRef][Medline]
87. Zadik Z, Chalew S, McCarter R, Meista M, Kowarski AA 1985 The influence of age in the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab 60:513–516[Abstract/Free Full Text]
88. Lee PA, Kowarski AA, Migeon CJ, Blizzard RM 1975 Lack of correlation between gonadotropin and adrenal androgen levels in agonadal children. J Clin Endocrinol Metab 40:664–669[Abstract/Free Full Text]
89. Sizonenko PC, Paunier L 1975 Hormonal changes in puberty. III. Correlation of plasma dehydroepiandrosterone, testosterone, FSH and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison’s disease or hypogonadism or premature or late adrenarche. J Clin Endocrinol Metab 41:894–899[Abstract/Free Full Text]
90. Genazzani A, Pintor C, Facchinetti F, Pintor C, Puggioni R, Parrini D, Petraglia F, Bagnoli F, Corda R 1979 POMC-related peptide plasma levels throughout prepuberty and puberty. J Clin Endocrinol Metab 57:56–61[Abstract/Free Full Text]
91. Genazzani A, Pintor C, Facchinetti F, Inaudi P, Maci D, Corda R 1979 Changes throughout puberty in adrenal secretion after ACTH. J Steroid Biochem 11:571–577[CrossRef][Medline]
92. Genazzani A, Pintor C, Facchinetti F, Carboni G, Pelosi U, Corda R 1978 Adrenal and gonadal steroids in girls during sexual maturation. Clin Endocrinol (Oxf) 8:15–25[Medline]
93. Freemark M, Driscoll P, Maaskant R, Petryk A, Kelly PA 1997 Ontogenesis of prolactin receptors in the human fetus in early gestation: implications for tissue differentiation and development. J Clin Invest 99:1107–1117[Medline]
94. Yamaji T, Ishibashi M, Takaku F, Teramoto A, Takakura K, Takami M, Fukushima T, Kamoi K 1989 Role of prolactin in age-related change in serum dehydroepiandrosterone sulphate concentrations. Acta Endocrinol (Copenh) 120:655–660[Abstract/Free Full Text]
95. Zogopoulos G, Albrecht S, Pietsch T, Alpert L, Von Schweinitz D, Lefebvre Y, Goodyer CG 1996 Fetal- and tumor-specific regulation of growth hormone receptor messenger RNA expression in human liver. Cancer Res 56:2949–2953[Abstract/Free Full Text]
96. Lin CJ, Mendonca BB, Lucon AM, Guazelli ICD, Nicolau W, Villares SMF 1997 Growth hormone receptor messenger ribonucleic acid in normal and pathologic human adrenocortical tissues: an analysis by quantitative polymerase chain reaction technique. J Clin Endocrinol Metab 82:2671–2676[Abstract/Free Full Text]
97. Smith RG, Pong SS, Hickey G, Jacks T, Cheng K, Leonard R, Cohen CJ, Arena JP, Chang CH, Drisko J, Wyvratt M, Fisher M, Nargund R, Patchett A 1996 Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland. Recent Prog Horm Res 51:261–285
98. Weber A, Clark AJ, Perry LA, Honour JW, Savage MO 1997 Diminished adrenal androgen secretion implies a significant role for ACTH in the induction of adrenarche. Clin Endocrinol (Oxf) 46:431–437[Medline]
99. Ghizzoni L, Virdis R, Ziveri M, Lamboglini A, Alberini A, Volta C, Bernasconi S 1989 Adrenal steroid, cortisol, adrenocorticotropin and ß-endorphin responses to human corticotropin-releasing hormone stimulation test in normal children and children with premature pubarche. J Clin Endocrinol Metab 69:875–880[Abstract/Free Full Text]
100. Ibáñez L, Potau N, Marcos MV, DeZegher F 1999 Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche. J Clin Endocrinol Metab 84:4602–2607[Abstract/Free Full Text]
101. Albertson B, Hobson W, Barnett B, Turner PT, Clark RV, Schiebinger RJ, Loriaux DL, Cutler Jr GB 1984 Dissociation of cortisol and adrenal androgen secretion in the hypophysectomized, ACTH-replaced chimpanzee. J Clin Endocrinol Metab 59:13–18[Abstract/Free Full Text]
102. Hauffa BP, Kaplan SL, Grumbach MM 1984 Dissociation between plasma adrenal androgens and cortisol in Cushing’s disease and ectopic ACTH-producing tumour: relation to adrenarche. Lancet 1:1373–1376[Medline]
103. Suda T, Demura H, Demura R, Jibiki K, Tozawa F, Shizuma F 1980 Anterior pituitary hormones in plasma and pituitary from patients with Cushing’s disease. J Clin Endocrinol Metab 51:1048–1053[Abstract/Free Full Text]
104. Chan JSD, Seidah NG, Chretien M 1983 Measurement of N-terminal (1–76) proopiomelanocortin in human plasma: correlation with adrenocorticotropin. J Clin Endocrinol Metab 56:791–796[Abstract/Free Full Text]
105. Parker LN, Lifrak ET, Odell WD 1983 A 60,000 molecular weight human pituitary glycopeptide stimulates adrenal androgen secretion. Endocrinology 113:2092–2096[Abstract/Free Full Text]
106. Parker L, Lifrak E, Shively J, Lee T, Kaplan B, Walker P, Calaycay J, Florsheim W, Soon-Shiong B 1989 Human gland cortical androgen-stimulating hormone (CASH) is identical with a portion of the joint peptide of pituitary proopiomelanocortin (POMC). Program of the 71st Annual Meeting of The Endocrine Society, Seattle, Washington, 1989, p 97 (Abstract)
107. Parker L, Lifrak E, Gelfand R, Shively J, Lee T, Kaplan B, Walker P, Calaycay J, Florsheim W, Mason I, Soong-Shiong P 1993 Isolation, purification, synthesis and binding of human adrenal gland cortical androgen stimulating hormone. Endocr J 1:441–445
108. Mellon SH, Shively JE, Miller WL 1991 Human proopiomelanocortin (9–96), a proposed androgen stimulating hormone, does not affect steroidogenesis in cultured human fetal adrenal cells. J Clin Endocrinol Metab 72:19–22[Abstract/Free Full Text]
109. Penhoat A, Sanchez P, Jaillard C, Langlois D, Begeot M 1991 Human proopiomelanocortin-(79–96), a proposed cortical androgen-stimulating hormone, does not affect steroidogenesis in cultured human adult adrenal cells. J Clin Endocrinol Metab 72:23–26[Abstract/Free Full Text]
110. Robinson P, Bateman A, Mulay S, Spencer SJ, Jaffe RB, Solomon S, Bennett HP 1991 Isolation and characterization of three forms of joining peptide from adult human pituitaries: lack of adrenal androgen-stimulating activity. Endocrinology 129:859–867[Abstract/Free Full Text]
111. Miller WL, Johnson LK 1982 Synthesis and glycosylation of pro- opiomelanocortin by a Cushing tumor. J Clin Endocrinol Metab 55:441–446[Abstract/Free Full Text]
112. Remer T, Marz F 1999 Role of nutritional status in the regulation of adrenarche. J Clin Endocrinol Metab 84:3936–3944[Abstract/Free Full Text]
113. Anderson DC 1978 The adrenal androgen-stimulated hormone does not exist. Lancet 2:454–456[Medline]
114. Couch RM, Muller J, Winter JSD 1986 Regulation of the activities of 17-hydroxylase and 17,20-desmolase in the human adrenal cortex: kinetic analysis and inhibition by endogenous steroids. J Clin Endocrinol Metab 63:613–618, 1986[Abstract/Free Full Text]
115. Byrne G, Perry Y, Winter JSD 1985 Kinetic analysis of adrenal 3ß- HSD activity during human development. J Clin Endocrinol Metab 60:934–939[Abstract/Free Full Text]
116. Schiebinger RJ, Albertson BD, Cassorla FG, Bowyer DW, Geelhoed GW, Cutler Jr GB, Loriaux DL 1981 The developmental changes in plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase. J Clin Invest 67:1177–1182
117. Rich B, Rosenfield R, Lucky A, Helke J, Otto P 1981 Adrenarche: changing adrenal response to adrenocorticotropin. J Clin Endocrinol Metab 52:1129–1134[Abstract/Free Full Text]
118. Kahri AI, Voutilainen R, Salmenperae M 1979 Different biological action of corticosteroids, corticosterone, and cortisol as a bases of zonal function adrenal cortex. Acta Endocrinol (Copenh) 91:329–337[Abstract/Free Full Text]
119. Gell JS, Carr BR, Sasano H, Atkins B, Margraf L, Mason JI, Rainey WE 1998 Adrenarche results from development of a 3ß-hydroxysteroid dehydrogenase-deficient adrenal reticularis. J Clin Endocrinol Metab 83:3695–3701[Abstract/Free Full Text]
120. L’Allemand D, Penhoat A, Lebrethon MC, Ardevol R, Baehr V, Oelkers W, Saez JM 1996 Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 81:3892–3897[Abstract/Free Full Text]
121. Lebrethon MC, Jaillard C, Naville D, Begeot M, Saez JM 1994 Effects of transforming growth factor-1 on human adrenocortical fasciculata- reticularis cell differentiated functions. J Clin Endocrinol Metab 79:1033–1039[Abstract]
122. Wolkersdörfer GW, Lohmann T, Marx C, Schröder S, Pfeiffer R, Stahl H-D, Scherbaum WA, Chrousos GP, Bornstein SR 1999 Lymphocytes stimulate dehydroepiandrosterone production through direct cellular contact with adrenal zona reticularis cells: a novel mechanism of immune-endocrine interaction. J Clin Endocrinol Metab 84:4220–4227[Abstract/Free Full Text]
123. Yanagibashi K, Hall PF 1980 Role of electron transport in the regulation of the lyase activity of C32 side-chain cleavage P-450 from porcine adrenal and testicular microsomes. J Biol Chem 261:8429–8433[Abstract/Free Full Text]
124. Lin D, Black SM, Nagahama Y, Miller WL 1993 Steroid 17-alpha-hydroxylase and 17,20-lyase activities of P450C17: contributions of serine 106 and P450 reductase. Endocrinology 132:2498–2506[Abstract/Free Full Text]
125. Geller DJ, Auchus RJ, Mendonca BB, Miller WL 1997 Molecular mechanism of 17,20-lyase deficiency. Horm Res 48[Suppl 2]:47 (Abstract)
126. Auchus RJ, Lee TC, Miller WL 1998 Cytochrome b5 augments the 17,20-lyase activity of human P450C17 without direct electron transfer. J Biol Chem 273:3158–3165[Abstract/Free Full Text]
127. Lin D, Zhang LH, Chiao E, Miller WL 1994 Modeling and mutagenesis of the active site of human P450C17. Mol Endocrinol 8:392–402[Abstract/Free Full Text]
128. Dunaif A 1997 Insulin resistance and the polycystic ovary syndrome: mechanisms and implications for pathogenesis. Endocr Rev 18:774–800[Abstract/Free Full Text]
129. Takayama S, White MF, Kahn CR 1988 Phorbol ester-induced serine phosphorylation of the insulin receptor decreases its tyrosine kinase activity. J Biol Chem 263:3440–3447[Abstract/Free Full Text]
130. Chin CE, Dickens M, Tavare JM, Roth RA 1993 Overexpression of protein kinase C isoenzymes , ß I, , and in cells over-expressing the insulin receptor: effects on receptor phosphorylation and signaling. J Biol Chem 268:6338–6347[Abstract/Free Full Text]
131. Sklar CA, Kaplan SL, Grumbach MM 1980 Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and development. J Clin Endocrinol Metab 51:548–556
132. Saenger P 1996 Turner’s syndrome. N Engl J Med 335:1749–1754[Free Full Text]
133. Counts DR, Pescovitz OH, Barnes KM, Hench KD, Chrousos GP, Sherin SR, Comité F, Loriaux DL, Cutler Jr GB 1987 Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism. J Clin Endocrinol Metab 64:1174–1178[Abstract/Free Full Text]
134. Urban M, Lee PA, Guta JP, Migeon CJ 1980 Androgens in pubertal males with Addison’s disease. J Clin Endocrinol Metab 5:925–929
135. Wilkins L 1948 Abnormalities and variations of sexual development during childhood and adolescence. In: Advances in Pediatrics. Interscience, New York, vol 3:159
136. Talbot NB, Sobel EH, McArthur JW, Crawford JD 1952 Precocious adrenarche. In: Case, Lockwood AS, Brainard M (eds) Functional Endocrinology from Birth through Adolescence. Commonwealth Fund, Harvard University, Cambridge, MA, pp 247–252
137. Sigurjonsdottir TJ, Hayles AS 1968 Premature pubarche. Clin Pediatr (Phila) 7:29–33
138. Liu N, Grumbach MM, deNapoli RA, Morishima A 1965 Prevalence of electro-encephalographic abnormalities in idiopathic precocious puberty and premature pubarche: bearing on pathogenesis and neuroendocrine regulation of puberty. J Clin Endocrinol Metab 25:1296–1308[Abstract/Free Full Text]
139. Thamdrup E 1955 Premature pubarche: a hypothalamic disorder? Report of 17 cases. Acta Endocrinol (Copenh) 18:564–567
140. Reiter EO, Kulin HF 1972 Sexual maturation in the female: normal development and precocious puberty. Pediatr Clin North Am 19:581–603[Medline]
141. Pang S 1984 Premature adrenarche. Pediatr Adolesc Endocrinol 13:173–184
142. Rosenbaum M, Leibel RL 1989 Obesity in childhood. Pediatr Rev 11:43–55[Abstract/Free Full Text]
143. Jabbar M, Pugliese M, Fort P, Becker B, Lifshitz F 1991 Excess weight and precocious pubarche in children: alterations of the adrenocortical hormones. J Am Coll Nutr 10:289–296[Abstract]
144. Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM 1997 Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings Network. Pediatrics 99:505–512[Abstract/Free Full Text]
144. Rosenfield RL, Bachrach LK, Chernausek SD, Gertner JM, Gottschalk G, Hardin DS, Pescovitz OH, Saenger P 2000 Current age of onset of puberty. Pediatrics 106:622
145. Rosenfield RL, Rich BH, Lucky AW 1982 Adrenarche as a cause of benign pseudopuberty in boys. J Pediatr 101:1005–1009[CrossRef][Medline]
146. Parker LN, Sack J, Fisher DA, Odell WD 1978 The adrenarche: prolactin, gonadotropins, adrenal androgens and cortisol. J Clin Endocrinol Metab 46:396–401[Abstract/Free Full Text]
147. Voutilainen R, Perheentupa J, Apter D 1983 Benign premature adrenarche: clinical features and serum steroid levels. Acta Paediatr Scand 72:707–711[Medline]
148. Ibáñez L, Bonnin MR, Zampolli M, Prat N, Alia PJ, Navarro MA 1995 Usefulness of an ACTH test in the diagnosis of non-classical 21-hydroxylase deficiency among children presenting with premature pubarche. Horm Res 44:51–56[Medline]
149. Rosenfield RL 1994 Normal and almost normal precocious variations in pubertal development: premature pubarche and premature thelarche revisited. Horm Res 41[Suppl 2]:7–13
150. Lee PA, Migeon CJ, Bias WB, Jones GS 1996 Familial hypersecretion of adrenal androgens transmitted as a dominant, non-HLA linked trait. Obstet Gynecol 69:259–264
151. Dickerman Z, Gant DR, Faiman C, Winter JSD 1984 Intraadrenal steroid concentration in man: zonal differences and developmental changes. J Clin Endocrinol Metab 59:1031–1036
152. Kaplowitz PB, Cockrell JL, Young RB 1986 Premature adrenarche. Clinical and diagnostic features. Clin Pediatr (Phila) 25:28–34
153. Lee PA, Gareis FJ 1976 Gonadotropin and sex steroid response to luteinizing-hormone-releasing hormone in patients with premature adrenarche. J Clin Endocrinol Metab 43:195–197[Abstract/Free Full Text]
154. Reiter EO, Kaplan SL, Conte FA, Grumbach MM 1975 Responsivity of pituitary gonadotropes to luteinizing hormone-releasing factor in idiopathic precocious puberty, precocious thelarche, precocious adrenarche, and in patients treated with medroxyprogesterone acetate. Pediatr Res 9:111–116[Medline]
155. Saenger P, Reiter EO 1992 Premature adrenarche: a normal variant of puberty? (editorial). J Clin Endocrinol Metab 74:236–238[CrossRef][Medline]
156. Pang S 1981 Precocious thelarche and premature adrenarche. Pediatr Ann 10:340–345
157. Ibáñez L, Virdis R, Potau N, Zampolli M, Ghizzoni L, Albisu MA, Carrascosa A, Bernasconi S, Vicens-Calvet E 1992 Natural history of premature pubarche: an auxological study. J Clin Endocrinol Metab 74:254–257[Abstract]
158. Baulieu EE 1996 Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol Metab 81:3147–3151[CrossRef][Medline]
159. Guazzo EP, Kirkpatrick PJ, Goodyer IM, Shiers HM, Herbert J 1996 Cortisol, dehydroepiandrosterone (DHEA) and DHEA sulfate in the cerebrospinal fluid of man: relation to blood levels and the effects of age. J Clin Endocrinol Metab 81:3951–3960[Abstract/Free Full Text]
160. Virdis R, Zampolli M, Ibáñez L, Ghizzoni L, Street ME, Vicens-Calvet E 1993 Il pubarca prematuro. Riv Ital Pediatr (IJP) 19:569–579
161. De Peretti E, Forest MG, Bertrand J 1980 Le sulfate de dehydroépiandrostérone plasmatique en endocrinologie pédiatrique. Arch Fr Pediatr 37:27–32
162. Ibáñez L, Potau N, Carrascosa A 1997 Androgens in adrenarche and pubarche. In: Azziz R, Nestler JE, Dewailly D (eds) Androgen Excess Disorders in Women. Lippincott-Raven, Philadelphia, pp 73–84
163. Doberne Y, Levine LS, New MI 1975 Elevated urinary testosterone and androstenediol in precocious adrenarche. Pediatr Res 9:794–797[Medline]
164. Riddick LM, Garibaldi LR, Wang ME, Senne AR, Klimah PE, Clark AT, Levine LS, Oberfield SE, Pang S 1991 3ß-Androstenediol glucuronide in premature and normal pubarche. J Clin Endocrinol Metab 72:46–50[Abstract/Free Full Text]
165. Balducci R, Finocchi G, Mangiantini A 1992 Lack of correlation between sex hormone binding globulin, adrenal and peripheral androgens in precocious adrenarche. J Endocrinol Invest 15:501–505[Medline]
166. Kohn B, Levine LS, Pollack MS, Pang S, Lorenzen F, Levy D, Lerner AJ, Rondanini GF, Dupont B, New MI 1982 Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 55:817–827[Abstract/Free Full Text]
167. Granoff AB, Chasalow FI, Blethen SL 1985 17-Hydroxyprogesterone responses to adrenocorticotropin in children with premature adrenarche. J Clin Endocrinol Metab 60:409–415[Abstract/Free Full Text]
168. Temeck JM, Pang S, Nelson C, New MI 1987 Genetic defects in steroidogenesis in premature pubarche. J Clin Endocrinol Metab 64:609–617[Abstract/Free Full Text]
169. Sakkal-Alkaddour H, Zhang L, Yang X, Chang YT, Kappy M, Slover RS, Jorgensen V, Pang S 1996 Studies of 3ß-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated 5-steroid levels. J Clin Endocrinol Metab 81:3961–3965[Abstract/Free Full Text]
170. New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, Dupont B, Stoner E, Levy DJ, Pang S, Levine LS 1983 Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab 57:320–325[Abstract/Free Full Text]
171. Siegel SF, Finegold DN, Urban MD, McVie R, Lee PA 1992 Premature pubarche: etiological heterogeneity? J Clin Endocrinol Metab 74:239–247[Abstract]
172. White PC, Curnow KM, Pascoe L 1994 Disorders of steroid 11-hydroxylase isozymes. Endocr Rev 15:421–438[Abstract/Free Full Text]
173. Balducci R, Boscherini B, Mangiantini A, Morellii M, Toscano V 1994 Isolated precocious pubarche: an approach. J Clin Endocrinol Metab 79:582–589[Abstract]
174. Leite MV, Mendonca BB, Arnhold IJ, Estefan V, Nunes C, Nicolau W, Bloise W 1991 Identification of nonclassical 21-hydroxylase deficiency in girls with precocious pubarche. J Endocrinol Invest 14:11–15[Medline]
175. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI 1985 High frequency of non-classical steroid 21-hydroxylase deficiency. Am J Hum Genet 37:650–667[Medline]
176. Azziz R, Dewailly D, Owerbach D 1994 Nonclassic adrenal hyperplasia: current concepts (clinical review). J Clin Endocrinol Metab 78:810–815[CrossRef][Medline]
177. Wedell A 1998 Molecular genetics of congenital adrenal hyperplasia (21-hydroxylase deficiency): implications for diagnosis, prognosis, and treatment. Acta Paediatr 87:159–164[CrossRef][Medline]
178. Tardy V, Carel JC, Forest MG, Nicolino M, Pugeat M, Raux-Demay MC, Morel Y 1996 Nonclassical forms of 21-hydroxylase deficiency revised by molecular biology (154 patients, French Collaborative Studies). Proceedings of the 10th International Congress of Endocrinology, San Francisco, CA (Abstract P2–737), p 589
179. Pang S, Lerner AJ, Stoner E, Levine LS, Oberfield SE, Engel I, New MI 1985 Late-onset adrenal steroid 3ß-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women. J Clin Endocrinol Metab 60:428–439[Abstract/Free Full Text]
180. Eldar-Geva T, Hurwitz A, Vecsei P, Palti Z, Milwidsky A, Rösler A 1990 Secondary biosynthetic defects in women with late-onset congenital adrenal hyperplasia. N Engl J Med 323:855–863[Abstract]
181. Chang YT, Zhang L, Alkaddour HS, Mason IJ, Lin K, Yang X, Garibaldi L, Bourdony C, DoLan LM, Donaldson DL 1995 Absence of molecular defect in the type II 3ß-hydroxysteroid dehydrogenase (3ß-HSD) gene in premature pubarche children and hirsute female patients with moderately decreased adrenal 3ß-HSD activity. Pediatr Res 37:820–824[Medline]
182. Lucky AW, Rosenfield RL, McGuire J, Rudy S, Helke J 1986 Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche. J Clin Endocrinol Metab 62:840–848[Abstract/Free Full Text]
183. Ibáñez L, Potau N, Zampolli M, Prat N, Gussinyé M, Saenger P, Vicens-Calvet E, Carrascosa A 1994 Source localization of androgen excess in adolescent girls. J Clin Endocrinol Metab 79:1778–1784[Abstract]
184. Likitmaskul S, Cowell CT, Donaghue K, Kreutzmann DJ, Howard NJ, Blades B, Silink M 1995 "Exaggerated adrenarche" in children presenting with premature pubarche. Clin Endocrinol (Oxf) 42:265–272[Medline]
185. Ehrmann DA, Rosenfield RL, Barnes RB, Brigell DF, Sheikh Z 1992 Detection of functional ovarian hyperandrogenism in women with androgen excess. N Engl J Med 327:157–162[Abstract]
186. Rosenfield RL 1996 Evidence that idiopathic functional adrenal hyperandrogenism is caused by dysregulation of adrenal steroidogenesis and that hyperinsulinemia may be involved (editorial). J Clin Endocrinol Metab 81:878–880[CrossRef][Medline]
187. Banerjee S, Raghavan S, Wasserman E, Linder B, Saenger P, DiMartino-Nardi J 1998 Hormonal findings in African American and Caribbean Hispanic girls with premature adrenarche: implications for polycystic ovarian syndrome. Pediatrics 102:E36
188. Barnes RB, Ehrmann DE, Brigell DF, Rosenfield RL 1993 Ovarian steroidogenic responses to gonadotropin-releasing hormone agonist testing with nafarelin in hirsute women with adrenal responses to adrenocorticotropin suggestive of 3-hydroxy-5-steroid dehydrogenase deficiency. J Clin Endocrinol Metab 76:450–456[Abstract]
189. Pere A, Voutilainen R, Perheentupa A, Peter M 1995 Follow-up of growth and steroids in premature adrenarche. Eur J Pediatr 154:346–352[CrossRef][Medline]
190. Yen SSC 1986 Chronic anovulation caused by peripheral endocrine disorders. In: Yen SCC, Jaffe RB (eds) Reproductive Endocrinology. Saunders, Philadelphia, pp 441–499
191. Rao JK, Chihal HJ, Johnson PL 1985 Primary polycystic ovary syndrome in a premenarcheal girl: a case report. J Reprod Med 30:361–365[Medline]
192. Bridges NA, Cooke A, Healy MJR, Hindmarsh PC, Brook CGD 1995 Ovaries in sexual precocity. Clin Endocrinol (Oxf) 42:135–140[Medline]
193. Ibáñez L, Potau N, Albisu M, Enriquez G, Gussinyé M, Carrascosa A, Vicens-Calvet E 1990 Post-puberal assessment in girls with premature pubarche: clinical, biochemical, and echographic findings. Horm Res 33 [Suppl 3]:37 (Abstract)
194. Ferriman D, Gallway JD 1961 Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447
195. Stein IF, Leventhal ML 1935 Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181–191
196. Yen SS 1980 The polycystic ovary syndrome. Clin Endocrinol (Oxf) 12:177–207[Medline]
197. Goldzieher JW, Green JA 1962 The polycystic ovary. I. Clinical and histologic features. J Clin Endocrinol Metab 22:325–338
198. Franks S 1995 Polycystic ovary syndrome. N Engl J Med 333:853–861[Free Full Text]
199. Ehrmann DA, Barnes RB, Rosenfield RL 1995 Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion. Endocr Rev 16:322–353[Abstract/Free Full Text]
200. Zawadzki JK, Dunaif A 1992 Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR (eds) Polycystic Ovary Syndrome. Blackwell, Boston, pp 377–384
201. Rosenfield RL 1997 Current concepts of polycystic ovary syndrome. Baillieres Clin Obstet Gynaecol 11:307–333[CrossRef][Medline]
202. De Fazio J, Meldrum DR, Lu JK, Vale WW, Rivier JE, Judd HL, Chang RJ 1985 Acute ovarian responses to a long-acting agonist of gonadotropin-releasing hormone in ovulatory women and women with polycystic ovarian disease. Fertil Steril 44:453–459[Medline]
203. Heber D, Bhasin S, Steiner B, Swerdloff RS 1984 The stimulatory and down-regulatory effects of a gonadotropin-releasing hormone agonist in man. J Clin Endocrinol Metab 58:1084–1088[Abstract/Free Full Text]
204. Barnes RB, Rosenfield RL, Burnstein S, Ehrmann DA 1989 Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome. N Engl J Med 320:559–565[Abstract]
205. Ehrmann DA, Rosenfield RL, Cuttler L, Burstein S, Cara JF, Levitsky LL 1989 A new test of combined pituitary-testicular function using the gonadotropin-releasing hormone agonist nafarelin in the differentiation of gonadotropin deficiency from delayed puberty: pilot studies. J Clin Endocrinol Metab 69:963–967[Abstract/Free Full Text]
206. Ibáñez L, Potau N, Zampolli M, Virdis R, Gussinyé M, Carrascosa A, Saenger P, Vicens-Calvet E 1994 Use of leuprolide acetate response patterns in the early diagnosis of pubertal disorders: comparison with the gonadotropin-releasing hormone test. J Clin Endocrinol Metab 78:30–35[Abstract]
207. Ibáñez L, Hall JE, Potau N, Carrascosa A, Prat N, Taylor AE 1996 Ovarian 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation testing. J Clin Endocrinol Metab 81:4103–4107[Abstract/Free Full Text]
208. Rosenfield RL, Barnes RB, Ehrmann DA 1994 Studies of the nature of 17- hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 79:1686–1692[Abstract]
209. Ibáñez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinyé M, Carrascosa A, Vicens-Calvet E 1993 Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1599–1603[Abstract]
210. Ibáñez L, Potau N, Georgopoulos N, Prat N, Gussinyé M, Carrascosa A 1995 Growth hormone, insulin-like growth factor-I axis and insulin secretion in hyperandrogenic adolescents. Fertil Steril 64:1113–1119[Medline]
211. Miller WL 1988 Molecular biology of steroid hormone synthesis. Endocr Rev 9:295–318[Abstract/Free Full Text]
212. Nobels F, Dewailly D 1992 Puberty and polycystic ovarian syndrome: the insulin/insulin-like growth factor I hypothesis. Fertil Steril 58:655–666[Medline]
213. Ibáñez L, Potau N, Zampolli M, Street ME, Carrascosa A 1997 Girls diagnosed with premature pubarche show an exaggerated ovarian androgen synthesis from the early stages of puberty: evidence from gonadotropin-releasing hormone agonist testing. Fertil Steril 67:849–855[CrossRef][Medline]
214. Ibáñez L, de Zegher F, Potau N 1999 Anovulation after precocious pubarche: early markers and time course in adolescence. J Clin Endocrinol Metab 84:2691–2695[Abstract/Free Full Text]
215. Ibáñez L, Potau N, Zampolli M, Marcos MV, Carrascosa A 1997 Functional adrenal hyperandrogenism is a common feature in postpubertal girls with a history of premature pubarche: relationship to hyperinsulinemia and ovarian androgen excess. Horm Res [Suppl 2]:110 (Abstract)
216. Amiel SA, Caprio S, Sherwin RS, Plewe G, Haymond MW, Tamborlane WV 1991 Insulin resistance of puberty: a defect restricted to peripheral glucose metabolism. J Clin Endocrinol Metab 72:277–282[Abstract/Free Full Text]
217. Caprio S, Plewe G, Diamond MP, Simonson DC, Boulware SD, Sherwin RS, Tamborlane WV 1989 Increased insulin secretion in puberty: a compensatory response to reductions in insulin sensitivity. J Pediatr 114:963–967[CrossRef][Medline]
218. Bloch CA, Clemons P, Sperling MA 1987 Puberty decreases insulin sensitivity. J Pediatr 110:481–487[CrossRef][Medline]
219. Smith CP, Archibald HR, Thomas JM, Tarn AC, Williams AJK, Gale EAM, Savage MO 1988 Basal and stimulated insulin levels rise with advancing puberty. Clin Endocrinol (Oxf) 28:7–14[Medline]
220. Hindmarsh P, Di Silvio L, Pringle PJ, Kurtz AB, Brook CGD 1988 Changes in serum insulin concentration during puberty and their relationship to growth hormone. Clin Endocrinol (Oxf) 28:381–388[Medline]
221. Holly JMP, Smith CP, Dunger DB, Howell RJS, Chard T, Perry LA, Savage MO, Cianfarani S, Rees LH, Wass JAH 1989 Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-1. A synchronized approach to pubertal development. Clin Endocrinol (Oxf) 31:277–284[Medline]
222. Argente J, Barrios V, Pozo J, Muñoz MT, Hervas F, Stene M, Hernández M 1993 Normative data for insulin-like growth factors (IGFs), IGF-binding proteins, and growth hormone-binding protein in healthy Spanish pediatric population: age- and sex-related changes. J Clin Endocrinol Metab 77:1522–1528[Abstract]
223. Potau N, Ibáñez L, Riqué S, Carrascosa A 1997 Pubertal changes in insulin secretion and peripheral insulin sensitivity. Horm Res 48:219–226[Medline]
224. Travers SH, Jeffers BW, Bloch CA, Hill JO, Eckel RH 1995 Gender and Tanner stage differences in body composition and insulin sensitivity in early pubertal children. J Clin Endocrinol Metab 80:172–178[Abstract]
225. Arslanian S, Suprasongsin C 1996 Differences in the in vivo insulin secretion an sensitivity of healthy black vs. white adolescents. J Pediatr 129:440–443[CrossRef][Medline]
226. Jiang X, Srinivasan SR, Radhakrishnamurthy B, Dalferes ER, Berenson GS 1996 Racial (Black-White) differences in insulin secretion and clearance in adolescents: The Bogalusa Heart Study. Pediatrics 97:357–360[Abstract/Free Full Text]
227. Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ 1986 Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab 62:904–910[Abstract/Free Full Text]
228. Cara JF, Rosenfield RL 1988 Insulin-like factor I and insulin potentiate luteinizing hormone-induced androgen synthesis by rat ovarian thecal-interstitial cells. Endocrinology 123:733–739[Abstract/Free Full Text]
229. Richards GE, Cavallo A, Meyer III WJ, Prince MJ, Peters EJ, Stuart CA, Smith ER 1985 Obesity, acanthosis nigricans, insulin resistance and hyperandrogenemia: pediatric perspective and natural history. J Pediatr 107:893–897[CrossRef][Medline]
230. Oppenheimer E, Linder B, DiMartino-Nardi J 1995 Decreased insulin sensitivity in prepubertal girls with premature pubarche and acanthosis nigricans. J Clin Endocrinol Metab 80:614–618[Abstract]
231. Cutfield WS, Bergman RN, Menon RK, Sperling MA 1990 The modified minimal model: application to measurement of insulin sensitivity in children. J Clin Endocrinol Metab 70:1644–1650[Abstract/Free Full Text]
232. Bergman RN, Finegood DT, Adar M 1985 Assessment of insulin sensitivity in vivo. Endocr Rev 6:45–86[Abstract/Free Full Text]
233. Suikkari AM, Koivisto VA, Rutanen EM, Yki-Jarvinen H, Karonen SL, Seppala M 1988 Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab 6:266–272
234. Vuguin P, Saenger P, DiMartino-Nardi J 1997 Linking the hyperandrogenism of benign premature adrenarche in children and polycystic ovarian syndrome in adults. In: Azziz R, Nestler JE, Dewailly D (eds) Androgen Excess Disorders in Women. Lippincott-Raven, Philadelphia, pp 435–440
235. Vuguin P, Linder B, Rosenfeld R, Saenger P, DiMartino-Nardi J 1999 The role of insulin sensitivity, insulin-like growth factor-I and insulin-like growth factor binding proteins 1 and 3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche. J Clin Endocrinol Metab 84:2037–2042[Abstract/Free Full Text]
236. Ibáñez L, Potau N, Zampolli M, RiquÈ S, Saenger P, Carrascosa A 1997 Hyperinsulinemia and decreased insulin-like growth factor binding protein-1 are common features in prepubertal and postpubertal girls with a history of premature pubarche. J Clin Endocrinol Metab 82:2283–2288[Abstract/Free Full Text]
237. Nestler JE 1993 Sex hormone-binding globulin: a marker for hyperinsulinemia and/or insulin resistance? (editorial). J Clin Endocrinol Metab 76:273–274[CrossRef][Medline]
238. Nestler JE, Clore JN, Strauss III JF, Blackard WG 1987 The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. J Clin Endocrinol Metab 64:180–184[Abstract/Free Full Text]
239. Jarvinen H, Makimattila S, Utrianen T, Rutanen E 1995 Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab 80:3227–3232[Abstract]
240. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1997 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183–1197
241. Haffner SM, Valdez RA, Morales PA, Hazuda HP, Stern MP 1993 Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men. J Clin Endocrinol Metab 77:56–60[Abstract]
242. Ibáñez L, Potau N, Carrascosa A 1998 Insulin resistance, premature adrenarche, and a risk of the polycystic ovary syndrome (POS). Trends Endocrinol Metab 9:72–77
242. Vuguin P, Saenger P, DiMartino-Nardi J 1999 Fasting insulin glucose ratio: a useful measure of insulin resistance in girls with premature adrenarch. Platform presentation. The Society for Pediatric Research, May 1–4, 1999, San Francisco, CA, Pediatr Res 45:99A
242. DiMartino-Nardi J 1999 Premature adrenarch: findings in prepubertal African-American and Caribbean-Hispanic girls. Acta Paediatr Suppl 433:1–6
243. O’ Meara NM, Blackman JD, Ehrmann DA, Barnes RB, Jaspan JB, Rosenfield RL, Polonsky KS 1993 Defects in ß-cell function in functional ovarian hyperandrogenism. J Clin Endocrinol Metab 76:1241–1247[Abstract]
244. Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A 1987 Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499–507[Abstract/Free Full Text]
245. Dunaif A, Segal KR, Futterweit W, Dobrjansky A 1989 Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 38:1165–1174[Abstract]
246. Chang RJ, Nakamura RM, Judd HL, Kaplan SA 1983 Insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 57:356–359[Abstract/Free Full Text]
247. Jialal I, Naiker P, Reddi K, Moodley J, Joubert SM 1987 Evidence for insulin resistance in nonobese patients with polycystic ovarian disease. J Clin Endocrinol Metab 64:1066–1069[Abstract/Free Full Text]
248. Nestler JE, Clore JN, Blackard WG 1989 The central role of obesity (hyperinsulinemia) in the pathogenesis of the polycystic ovary syndrome. Am J Obstet Gynecol 161:1095–1097[Medline]
249. Falcone T, Finegood DT, Fantus G, Morris D 1990 Androgen response to endogenous insulin secretion during the frequently sampled intravenous glucose tolerance test in normal and hyperandrogenic women. J Clin Endocrinol Metab 71:1653–1657[Abstract/Free Full Text]
250. Tropeano G, Lucisano A, Liberale I, Barini A, Vuolo IP, Martino G, Menini E, Dell’Acqua S 1994 Insulin C-peptide, androgens, and ß-endorphin response to oral glucose in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 78:305–309[Abstract]
251. Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS 1995 Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus. J Clin Invest 96:520–527
252. Dunaif A, Finegood DT 1996 ß-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:942–947[Abstract]
253. Toscano V, Bianchi P, Balducci R, Guglielmi R, Mangiantini A, Lubrano C, Sciarra F 1992 Lack of linear relationship between hyperinsulinemia and hyperandrogenism. Clin Endocrinol (Oxf) 36:197–202[Medline]
254. Dunaif A 1995 Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non-insulin-dependent diabetes mellitus. Am J Med 98[Suppl 1A]:33S–39S
255. Dunaif A, Sorbara L, Delson R, Green G 1993 Ethnicity and polycystic ovary syndrome are associated with independent and additive decreases in insulin action in Caribbean-Hispanic women. Diabetes 42:1462–1468[Abstract]
256. Norman RJ, Mahabeer S, Masters S 1995 Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome. Fertil Steril 63:58–62[Medline]
257. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA 1992 Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807–1812[Medline]
258. Poretsky L 1991 On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev 12:3–13[Abstract/Free Full Text]
259. Burghen GA, Givens JR, Kitabchi AE 1980 Correlation of hyperandrogenism with hyperinsulinism in polycystic ovarian disease. J Clin Endocrinol Metab 50:113–116[Abstract/Free Full Text]
260. Polderman KH, Gooren LJG, Asscheman H, Bakker A, Heine RJ 1994 Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265–271[Abstract]
261. Geffner ME, Kaplan SA, Bersch N, Golde DW, Landaw EM, Chang RJ 1986 Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril 45:327–333[Medline]
262. Dunaif A, Green G, Futterweit W, Dobrjansky A 1990 Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 70:699–704[Abstract/Free Full Text]
263. Elkind-Hirsch KE, Valdes CT, Malinak LR 1993 Insulin resistance improves in hyperandrogenic women treated with Lupron. Fertil Steril 60:634–641[Medline]
264. Moghetti P, Tosi F, Castello R, Magnani CM, Negri C, Brun E, Furlani L, Caputo M, Muggeo M 1996 The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 81:952–960[Abstract]
265. Dunaif A 1992 Insulin resistance and ovarian dysfunction. The Endocrinologist 2:248–260
266. Dunaif A, Graf M 1989 Insulin administration alters gonadal steroid metabolism independent of changes in gonadotropin secretion in insulin-resistant women with the polycystic ovary syndrome. J Clin Invest 83:23–29
267. Nestler JE, Barlascini CO, Matt DW, Matt DW, Steinglod KA, Plymate SR, Clore JN, Blackard WG 1989 Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 68:1027–1032[Abstract/Free Full Text]
268. Prelevic GM, Wurzburger MI, Balint-Peric L, Nesic JS 1990 Inhibitory effects of sandostatin on secretion of luteinizing hormone and ovarian steroids in polycystic ovary syndrome. Lancet 336:900–903[CrossRef][Medline]
269. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R 1996 The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299–3306[Abstract]
270. Nestler JE, Jakubowicz DJ 1996 Decreases in ovarian cytochrome P450C17 activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–623[Abstract/Free Full Text]
271. Nestler JE, Jakubowicz DJ, Falcon A, De Vargas CB, Quintero N, Medina F 1998 Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 93:2001–2005
272. Ibáñez L, Potau N, Zampolli M, Prat N, Virdis R, Vicens-Calvet E, Carrascosa A 1996 Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab 81:1237–1243[Abstract]
272. Grinstein GP, DiMartino-Nardi J Pubertal outcome of African American (AA) and Caribbean Hispanic (CH) adolescent girls with a history of premature adrenarche (PA). Abstract presented at the 82nd Annual Meeting of The Endocrine Society, June 21–26, 2000, Toronto, Canada, p 523
273. Norman RJ, Masters S, Hague W 1996 Hyperinsulinemia is common in family members of women with polycystic ovary syndrome. Fertil Steril 66:942–947[Medline]
274. Ibáñez L, Castell C, Tresserras R, Potau N 1999 Increased prevalence of unknown type 2 diabetes mellitus and impaired glucose tolerance in first-degree relatives of girls with a history of precocious pubarche. Clin Endocrinol (Oxf) 51:395–401[CrossRef][Medline]
275. Desprès JP, Lamarche B, Mauriège Cantin B, Dagenais G, Moorjani S, Lupien PJ 1996 Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952–957[Abstract/Free Full Text]
276. Reaven GM, Laws A 1994 Insulin resistance, compensatory hyperinsulinemia and coronary heart disease. Diabetologia 37:948–952[Medline]
277. Stern MP 1994 The insulin resistance syndrome: the controversy is dead, long live the controversy. Diabetologia 37:956–958[Medline]
278. Ibáñez L, Potau N, Chacon P, Pascual C, Carrascosa A 1998 Hyper-insulinemia, dyslipemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 41:1057–1063[CrossRef][Medline]
279. Arslanian S, Suprasongsin C 1996 Insulin sensitivity, lipids, and body composition in childhood: is "Syndrome X" present? J Clin Endocrinol Metab 81:1058–1062[Abstract]
280. Zimmet PZ, Collins VR, Dowse GK, Knight LT 1992 Hyperinsulinemia in youth is a predictor of type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35:534–541[CrossRef][Medline]
281. Fine RM 1991 Acanthosis nigricans. Int J Dermatol 30:17–18[Medline]
282. Kahn CR, Flier JS, Bar RS, Archer JA, Gorden P, Martin MM, Roth J 1976 The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 294:739–745[Abstract]
283. Barbieri RL, Ryan KJ 1983 Hyperandrogenism, insulin resistance, acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 147:90–101[Medline]
284. Barbieri RL 1994 Hyperandrogenism, insulin resistance and acanthosis nigricans. 10 years of progress. J Reprod Med 39:327–336[Medline]
285. Stuart CA, Pate CJ, Peters EJ 1989 Prevalence of acanthosis nigricans in an unselected population. Am J Med 87:269–272[Medline]
286. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JR 1985 Acanthosis nigricans in obese women with hyperandrogenism. Characterization of an insulin-resistant state distinct from the type A and B syndromes. Diabetes 34:101–107[Abstract]
287. Stuart CA, Peters EJ, Prince MJ, Richards G, Cavallo A, Meyer WJ 1986 Insulin resistance with acanthosis nigricans: the roles of obesity and androgen excess. Metabolism 35:197–205[CrossRef][Medline]
288. Grasinger CC, Wild RA, Parker IJ 1993 Vulvar acanthosis nigricans: a marker for insulin resistance in hirsute women. Fertil Steril 59:583–586[Medline]
289. Hud JA, Cohen JB, Wagner JM, Cruz PD 1992 Prevalence and significance of acanthosis nigricans in an adult obese population. Arch Dermatol 128:941–944[Abstract/Free Full Text]
290. Miller WL 1997 Pathophysiology, genetics and treatment of hyperandrogenism. Pediatr Clin North Am 44:375–395[CrossRef][Medline]
291. Dunaif A, Xia J, Book CB, Schenker E, Tang Z 1995 Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 96:801–810
292. Kramer RE, Buster JE, Anderson RN 1990 Differential modulation of ACTH-stimulated cortisol and androstenedione secretion by insulin. J Steroid Biochem 36:33–42[CrossRef][Medline]
293. O’Connell Y, McKenna TJ, Cunningham SK 1994 The effect of prolactin, human chorionic gonadotropin, insulin and insulin-like growth factor 1 on adrenal steroidogenesis in isolated guinea-pig adrenal cells. J Steroid Biochem 48:235–240
294. Cara JF, Fan J, Azzarello J, Rosenfield RL 1990 Insulin-like growth factor-I enhances luteinizing hormone binding to rat ovarian theca-interstitial cells. J Clin Invest 86:560–565
295. Willis D, Franks S 1995 Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. J Clin Endocrinol Metab 80:3788–3790[Abstract]
296. Moghetti P, Castello R, Negri C, Tosi F, Spiazzi GG, Brun E, Balducci R, Toscano V, Muggeo M 1996 Insulin infusion amplifies 17ß-hydroxycorticosteroid intermediates response to adrenocorticotropin in hyperandrogenic women: apparent relative impairment of 17,20-lyase activity. J Clin Endocrinol Metab 81:881–886[Abstract]
297. Norman RJ, Masters SC, Hague WM, Beng C, Pannall P, Wang JX 1995 Metabolic approaches to the subclassification of polycystic ovary syndrome. Fertil Steril 63:329–335[Medline]
298. Legro RS 1995 The genetics of polycystic ovary syndrome. Am J Med 98 [Suppl 1A]:9S–16S
299. Givens JR 1988 Familial polycystic ovarian disease. Endocrinol Metab Clin North Am 17:1–17
300. Lunde O, Magnus P, Sandvik L, Hoglo S 1989 Familial clustering in the polycystic ovarian syndrome. Gynecol Obstet Invest 28:23–30[Medline]
301. Hague WM, Adams J, Reeder ST, Peto TE, Jacobs HS 1988 Familial polycystic ovaries: a genetic disease. Clin Endocrinol (Oxf) 29:593–605[Medline]
302. Jahanfar S, Eden JA, Warren P, Seppala M, Nguyen TV 1995 A twin study of polycystic ovary syndrome. Fertil Steril 63:478–486[Medline]
303. Carey AH, Chan KL, Short F, White D, Williamson R, Franks S 1993 Evidence for a single gene effect causing polycystic ovaries and male pattern baldness. Clin Endocrinol (Oxf) 38:653–658[Medline]
304. Carey AH, Waterworth DM, Patel K, White D, Little J, Novelli P, Franks S, Williamson R 1994 Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17. Hum Mol Genet 3:1873–1876[Abstract/Free Full Text]
305. Gharani N, Waterworth DM, Williamson R, Franks S 1996 5' Polymorphism of the CYP17 gene is not associated with serum testosterone levels in women with polycystic ovaries (letter). J Clin Endocrinol Metab. 81:4174
306. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R 1997 Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 349:986–990[CrossRef][Medline]
307. Bennett ST, Lucassen AM, Gough SCL 1995 Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284–292[CrossRef][Medline]
308. Kennedy GC, German MS, Rutter WJ 1995 The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet 9:293–298[CrossRef][Medline]
309. Gharani N, Waterworth D, Batty S, White D, Gilling-Smith C, Conway GS, McCarthy M, Franks S, Williamson R 1997 Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism. Hum Mol Genet 6:397–402[Abstract/Free Full Text]
310. Knochenhauer ES, Cortet-Rudelli C, Cunningham RD, Conway-Myers BA, Dewailly D, Azziz R 1997 Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism. J Clin Endocrinol Metab 82;479–485
311. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, Strauss III JF, Spielman RS, Dunaif A 1999 Thirty seven candidate genes for polycyctic ovary syndrome: strongest evidence for linkage is with follistatin. Proc Natl Acad Sci 96:8573–8578[Abstract/Free Full Text]
312. Naeye RL 1965 Malnutrition: probable cause of fetal growth retardation. Arch Pathol 79:284–291
313. Turnispeed MR, Bentley K, Reynolds JW 1976 Serum dehydroepiandrosterone sulfate in premature infants and infants with intrauterine growth retardation. J Clin Endocrinol Metab 36:576–581[Abstract/Free Full Text]
314. Reynolds JW, Mirkin BL 1973 Urinary steroid levels in newborn infants with intrauterine growth retardation. J Clin Endocrinol Metab 36:576–581
315. Barker DJP, Gluckman PD, Godney KM, Harding JE, Owens JA, Robinson JS 1993 Fetal nutrition and cardiovascular disease in adult life. Lancet 341:938–941[CrossRef][Medline]
316. Barker DJP, Hales CN, Fall GH, Osmond C, Phillips K, Clark PM 1993 Type 2 diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36:62–67[CrossRef][Medline]
317. Francois I, de Zegher F 1997 Adrenarche and fetal growth. Pediatr Res 41:440–442[Medline]
318. Ibáñez L, Potau N, Francois I, de Zegher F 1998 Precocious pubarche, hyperinsulinism and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab 83:3558–3662[Abstract/Free Full Text]
319. Ibáñez L, Potau N, de Zegher F 1999 Premature pubarche, dyslipidemia and low IGFBP-1 in girls: relation to reduced prenatal growth. Pediatr Res 46:320–322[Medline]
320. Ibáñez L, Potau N, de Zegher F 1998 Premature pubarche, ovarian hyperandrogenism, hyperinsulinism and the polycystic ovary syndrome: from a complex constellation to a simple sequence of prenatal onset. J Endocrinol Invest 21:558–566[Medline]
321. Potau N, Ibáñez L, Sanchez-Ufarte C, Rique S, de Zegher F 1999 Pronounced adrenarche and precocious pubarche in boys. Horm Res 51:238–241[CrossRef][Medline]
322. de Zegher F, Francois I, Boehmer ALM, Saggese G, Muller J, Hiort O, Sultan C, Clayton P, Brauner R, Cacciari E, Ibanez L, Van Vliet G, Tiulpakov A, Saka N, Ritzen M, Sippell WG 1998 Androgens and fetal growth. Horm Res 50:243–244
323. Bloom W, Fawcett DW 1986 Textbook of Histology, ed 9. Saunders, Philadelphia, p 461

This article has been cited by other articles:

				P. Utriainen, J. Jaaskelainen, A. Saarinen, E. Vanninen, O. Makitie, and R. Voutilainen Body Composition and Bone Mineral Density in Children with Premature Adrenarche and the Association of LRP5 Gene Polymorphisms with Bone Mineral Density J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4144 - 4151. [Abstract] [Full Text] [PDF]

				M. Maliqueo, T. Sir-Petermann, V. Perez, B. Echiburu, A. Ladron de Guevara, C. Galvez, N. Crisosto, and R. Azziz Adrenal Function during Childhood and Puberty in Daughters of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3282 - 3288. [Abstract] [Full Text] [PDF]

				J.-B. Armengaud, M.-L. Charkaluk, C. Trivin, V. Tardy, G. Breart, R. Brauner, and M. Chalumeau Precocious Pubarche: Distinguishing Late-Onset Congenital Adrenal Hyperplasia from Premature Adrenarche J. Clin. Endocrinol. Metab., August 1, 2009; 94(8): 2835 - 2840. [Abstract] [Full Text] [PDF]

				C. Noordam, V. Dhir, J. C. McNelis, F. Schlereth, N. A. Hanley, N. Krone, J. A. Smeitink, R. Smeets, F. C.G.J. Sweep, H. L. C.-v. d. Grinten, et al. Inactivating PAPSS2 Mutations in a Patient with Premature Pubarche N. Engl. J. Med., May 28, 2009; 360(22): 2310 - 2318. [Abstract] [Full Text] [PDF]

				P. Utriainen, R. Voutilainen, and J. Jaaskelainen Continuum of phenotypes and sympathoadrenal function in premature adrenarche Eur. J. Endocrinol., April 1, 2009; 160(4): 657 - 665. [Abstract] [Full Text] [PDF]

				G. Binder, S. Weber, M. Ehrismann, N. Zaiser, C. Meisner, M. B. Ranke, L. Maier, S. A. Wudy, M. F. Hartmann, U. Heinrich, et al. Effects of Dehydroepiandrosterone Therapy on Pubic Hair Growth and Psychological Well-Being in Adolescent Girls and Young Women with Central Adrenal Insufficiency: A Double-Blind, Randomized, Placebo-Controlled Phase III Trial J. Clin. Endocrinol. Metab., April 1, 2009; 94(4): 1182 - 1190. [Abstract] [Full Text] [PDF]

				A. D. Nguyen, C. J. Corbin, J. C. Pattison, I. M. Bird, and A. J. Conley The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) Is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques Endocrinology, April 1, 2009; 150(4): 1748 - 1756. [Abstract] [Full Text] [PDF]

				G. P. August, S. Caprio, I. Fennoy, M. Freemark, F. R. Kaufman, R. H. Lustig, J. H. Silverstein, P. W. Speiser, D. M. Styne, and V. M. Montori Prevention and Treatment of Pediatric Obesity: An Endocrine Society Clinical Practice Guideline Based on Expert Opinion J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4576 - 4599. [Abstract] [Full Text] [PDF]

				M. Demissie, M. Lazic, E. M. Foecking, F. Aird, A. Dunaif, and J. E. Levine Transient prenatal androgen exposure produces metabolic syndrome in adult female rats Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E262 - E268. [Abstract] [Full Text] [PDF]

				Z Hochberg Juvenility in the context of life history theory Arch. Dis. Child., June 1, 2008; 93(6): 534 - 539. [Abstract] [Full Text] [PDF]

				S. Lappalainen, P. Utriainen, T. Kuulasmaa, R. Voutilainen, and J. Jaaskelainen Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1304 - 1309. [Abstract] [Full Text] [PDF]

				P. Utriainen, J. Jaaskelainen, J. Romppanen, and R. Voutilainen Childhood Metabolic Syndrome and Its Components in Premature Adrenarche J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4282 - 4285. [Abstract] [Full Text] [PDF]

				N. Crisosto, E. Codner, M. Maliqueo, B. Echiburu, F. Sanchez, F. Cassorla, and T. Sir-Petermann Anti-Mullerian Hormone Levels in Peripubertal Daughters of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2739 - 2743. [Abstract] [Full Text] [PDF]

				R. L. Rosenfield Identifying Children at Risk for Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 787 - 796. [Abstract] [Full Text] [PDF]

				J. M. Lee, D. Appugliese, N. Kaciroti, R. F. Corwyn, R. H. Bradley, and J. C. Lumeng Weight Status in Young Girls and the Onset of Puberty Pediatrics, March 1, 2007; 119(3): e624 - e630. [Abstract] [Full Text] [PDF]

				M. Corton, J. I. Botella-Carretero, A. Benguria, G. Villuendas, A. Zaballos, J. L. San Millan, H. F. Escobar-Morreale, and B. Peral Differential Gene Expression Profile in Omental Adipose Tissue in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 328 - 337. [Abstract] [Full Text] [PDF]

				S.K. Blank, C.R. McCartney, and J.C. Marshall The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2006; 12(4): 351 - 361. [Abstract] [Full Text] [PDF]

				E. Ortega, J. Koska, A. D. Salbe, P. A. Tataranni, and J. C. Bunt Serum {gamma}-Glutamyl Transpeptidase Is a Determinant of Insulin Resistance Independently of Adiposity in Pima Indian Children J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1419 - 1422. [Abstract] [Full Text] [PDF]

				T. D. Nebesio and E. A. Eugster Pubic Hair of Infancy: Endocrinopathy or Enigma? Pediatrics, March 1, 2006; 117(3): 951 - 954. [Abstract] [Full Text] [PDF]

				S Zukauskaite, D Lasiene, L Lasas, B Urbonaite, and P Hindmarsh Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls Arch. Dis. Child., September 1, 2005; 90(9): 932 - 936. [Abstract] [Full Text] [PDF]

				C. J. Petry, K. K. Ong, K. F. Michelmore, S. Artigas, D. L. Wingate, A. H. Balen, F. de Zegher, L. Ibanez, and D. B. Dunger Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women Hum. Reprod., July 1, 2005; 20(7): 1837 - 1843. [Abstract] [Full Text] [PDF]

				H. F. Escobar-Morreale, M. Luque-Ramirez, and J. L. San Millan The Molecular-Genetic Basis of Functional Hyperandrogenism and the Polycystic Ovary Syndrome Endocr. Rev., April 1, 2005; 26(2): 251 - 282. [Abstract] [Full Text] [PDF]

				T. Remer, K. R. Boye, M. F. Hartmann, and S. A. Wudy Urinary Markers of Adrenarche: Reference Values in Healthy Subjects, Aged 3-18 Years J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2015 - 2021. [Abstract] [Full Text] [PDF]

				K A Neville and J L Walker Precocious pubarche is associated with SGA, prematurity, weight gain, and obesity Arch. Dis. Child., March 1, 2005; 90(3): 258 - 261. [Abstract] [Full Text] [PDF]

				K. K. Ong, N. Potau, C. J. Petry, R. Jones, A. R. Ness, J. W. Honour, F. de Zegher, L. Ibanez, and D. B. Dunger Opposing Influences of Prenatal and Postnatal Weight Gain on Adrenarche in Normal Boys and Girls J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2647 - 2651. [Abstract] [Full Text] [PDF]

				D. D. Martin, R. Schweizer, C. P. Schwarze, M. W. Elmlinger, M. B. Ranke, and G. Binder The Early Dehydroepiandrosterone Sulfate Rise of Adrenarche and the Delay of Pubarche Indicate Primary Ovarian Failure in Turner Syndrome J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1164 - 1168. [Abstract] [Full Text] [PDF]

				V. H. Boonstra, P. G. H. Mulder, F. H. de Jong, and A. C. S. Hokken-Koelega Serum Dehydroepiandrosterone Sulfate Levels and Pubarche in Short Children Born Small for Gestational Age before and during Growth Hormone Treatment J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 712 - 717. [Abstract] [Full Text] [PDF]

				T. M. Plant and M. L. Barker-Gibb Neurobiological mechanisms of puberty in higher primates Hum. Reprod. Update, January 1, 2004; 10(1): 67 - 77. [Abstract] [Full Text] [PDF]

				L. Ibanez, K. K. Ong, N. Mongan, J. Jaaskelainen, M. V. Marcos, I. A. Hughes, F. de Zegher, and D. B. Dunger Androgen Receptor Gene CAG Repeat Polymorphism in the Development of Ovarian Hyperandrogenism J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3333 - 3338. [Abstract] [Full Text] [PDF]

				L. K. Midyett, W. V. Moore, and J. D. Jacobson Are Pubertal Changes in Girls Before Age 8 Benign? Pediatrics, January 1, 2003; 111(1): 47 - 51. [Abstract] [Full Text] [PDF]

				M. R. Denburg, M. E. Silfen, A. M. Manibo, D. Chin, L. S. Levine, M. Ferin, D. J. McMahon, C. Go, and S. E. Oberfield Insulin Sensitivity and the Insulin-Like Growth Factor System in Prepubertal Boys with Premature Adrenarche J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5604 - 5609. [Abstract] [Full Text] [PDF]

				L. Ibanez, N. Potau, A. Ferrer, F. Rodriguez-Hierro, M. V. Marcos, and F. de Zegher Anovulation in Eumenorrheic, Nonobese Adolescent Girls Born Small for Gestational Age: Insulin Sensitization Induces Ovulation, Increases Lean Body Mass, and Reduces Abdominal Fat Excess, Dyslipidemia, and Subclinical Hyperandrogenism J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5702 - 5705. [Abstract] [Full Text] [PDF]

				C. H. Gravholt, R. W. Naeraa, K. Brixen, K. W. Kastrup, L. Mosekilde, J. O. L. Jorgensen, and J. S. Christiansen Short-Term Growth Hormone Treatment in Girls With Turner Syndrome Decreases Fat Mass and Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Pediatrics, November 1, 2002; 110(5): 889 - 896. [Abstract] [Full Text] [PDF]

				C. Battaglia, G. Regnani, F. Mancini, L. Iughetti, S. Bernasconi, A. Volpe, C. Flamigni, and S. Venturoli Isolated Premature Pubarche: Ultrasonographic and Color Doppler Analysis--A Longitudinal Study J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3148 - 3154. [Abstract] [Full Text] [PDF]

				L. Ibanez, N. Potau, A. Ferrer, F. Rodriguez-Hierro, M. V. Marcos, and F. de Zegher Reduced Ovulation Rate in Adolescent Girls Born Small for Gestational Age J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3391 - 3393. [Abstract] [Full Text] [PDF]

				R Viner Splitting hairs Arch. Dis. Child., January 1, 2002; 86(1): 8 - 10. [Full Text] [PDF]

				L. Ibanez, K. Ong, N. Potau, M. V. Marcos, F. de Zegher, and D. Dunger Insulin Gene Variable Number of Tandem Repeat Genotype and the Low Birth Weight, Precocious Pubarche, and Hyperinsulinism Sequence J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5788 - 5793. [Abstract] [Full Text] [PDF]

				T. Remer and F. Manz The Midgrowth Spurt in Healthy Children Is Not Caused by Adrenarche J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4183 - 4186. [Abstract] [Full Text] [PDF]

				M. R. Palmert, D. L. Hayden, M. J. Mansfield, J. F. Crigler Jr., W. F. Crowley Jr., D. W. Chandler, and P. A. Boepple The Longitudinal Study of Adrenal Maturation during Gonadal Suppression: Evidence That Adrenarche Is a Gradual Process J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4536 - 4542. [Abstract] [Full Text] [PDF]

				L. Ibanez, C. Valls, A. Ferrer, M. V. Marcos, F. Rodriguez-Hierro, and F. de Zegher Sensitization to Insulin Induces Ovulation in Nonobese Adolescents with Anovulatory Hyperandrogenism J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3595 - 3598. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ibáñez, L. Articles by Saenger, P. Search for Related Content PubMed PubMed Citation Articles by Ibáñez, L. Articles by Saenger, P.