Original Article

www.jpedhc.org

Premature Adrenarche
Alexander K.C. Leung, MBBS, FRCPC, FRCP(UK & Irel), FRCPCH, FAAP, & Wm. Lane M. Robson, MD, FRCPC, FRCP(Glasg)

ABSTRACT Premature adrenarche refers to the precocious secretion of adrenal androgens, which results in the isolated development of pubic hair (pubarche) before the age of eight years in girls and nine years in boys. The female to male ratio is approximately 10:1. Dark, coarse and curly hair is limited initially to the labia majora in girls and to the root of the penis in boys. The hair extends gradually into the pubic region. Axillary hair, increased body odor, and acne can also be present. Hirsutism, deepening of the voice, clitoral enlargement, breast development, and phallic or testicular enlargement are characteristically absent. A transient acceleration of growth is common but nal height is usually not affected. The onset of puberty usually occurs at the normal age. Premature adrenarche can be a forerunner of polycystic ovary syndrome and/or syndrome X. Continued observation and periodic re-evaluation is necessary. J Pediatr Health Care. (2008) 22, 230-233. Key words: Premature adrenarche, pubarche, polycystic ovary syndrome, syndrome X

Alexander K. C. Leung is Clinical Associate Professor of Pediatrics, the University of Calgary, and Pediatric Consultant, the Alberta Childrens Hospital, Calgary, Alberta, Canada. Wm. Lane M. Robson is Medical Director, The Childrens Clinic, Calgary, Alberta, Canada. Correspondence: Alexander K. C. Leung, MBBS, FRCPC, FRCP(UK & Irel), FRCPCH, FAAP, #200, 233 - 16th Ave NW, Calgary, Alberta, Canada T2M 0H5; e-mail: aleung@ucalgary.ca. 0891-5245/$34.00 Copyright 2008 by the National Association of Pediatric Nurse Practitioners. doi:10.1016/j.pedhc.2007.07.002

INTRODUCTION Adrenarche refers to the puberty of the adrenal gland (Ibanez, DiMartino-Nardi, Potau, & Saenger, 2000). The condition is characterized by activation of adrenal androgen production and by impressive increases in dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone (Guven, Cinaz, & Ayvali, 2005; Ibanez et al.). Adrenarche is an enigmatic phenomenon that occurs only in humans and some higher primate species such as the chimpanzee and gorilla (Auchus & Rainey, 2004; Saenger & DiMartino-Nardi, 2001). Premature or precocious adrenarche refers to an earlier than normal secretion of adrenal androgens that results in an isolated development of pubic hair (pubarche) before 8 years of age in girls and 9 years in boys, without the appearance of other signs of sexual maturation (Ibanez et al.; Saenger & DiMartino-Nardi). Precocious development of pubic hair can cause embarrassment to the child and anxiety to the parents. Clinicians should be concerned because premature adrenarche can be the rst overt sign of an androgen-secreting tumor of a gonad or adrenal gland, congenital adrenal hyperplasia, or true precocious puberty. Recent studies suggest that premature adrenarche in some girls can be a forerunner of polycystic ovary syndrome and/or syndrome X (Andiran, Yordam, & Kirazh, 2005; Dorn & Rotenstein, 2004; Saenger & DiMartino-Nardi, 2001). EPIDEMIOLOGY Premature adrenarche is uncommon. In a cross-sectional study of 1231 school girls of Eastern European origin, only 2 (0.8%) of 255 girls aged 7 to 7.9 years were found to have premature adrenarche (Zukauskaite, Lasiene, Lasas, Urbonaite, & Hindmarch, 2005).
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. . . premature adrenarche can be the rst overt sign of an androgen-secreting tumor of a gonad or adrenal gland, congenital adrenal hyperplasia, or true precocious puberty.

FIGURE 1. A 6-year-old girl with isolated development of pubic hair. This gure can be viewed in color on the Web at www.jpedhc.org.

Black children are affected much more frequently than are White children (Banerjee et al., 1998). The female-to-male ratio is approximately 10:1 (Dorn & Rotenstein, 2004; Saenger & DiMartino-Nardi, 2001). Both prematurity and intrauterine growth retardation might predispose to premature adrenarche in a susceptible individual (Charkaluk, Trivin, & Brauner, 2004; Neville & Walker, 2005). Excess weight gain might be a trigger for adrenarche, and obesity is reported to be associated with a higher incidence of premature adrenarche (Ibanez et al., 2000; Leung & Robson, in press; Neville & Walker, 2005; Remer, 2000). The occurrence of premature adrenarche usually is sporadic, although familial occurrence also has been described (Leung, 1989). PATHOGENESIS Adrenarche begins several years before the onset of gonadal maturation and correlates with the appearance of the zona reticularis of the adrenal gland. Adrenarche is independent of gonadarche and proceeds even in persons with gonadal dysgenesis. In normal puberty, adrenarche and gonadarche are closely linked. Premature adrenarche is secondary to an early isolated maturation of the zona reticularis with an increase in adrenal androgen secretion for the chronologic age but with normal glucocorticoid levels (Azziz et al., 2004; Meas et al., 2002). Oversecretion of adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH) per se cannot account for premature
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adrenarche because ACTH always causes a greater increase in corticosteroids than in androgens. In patients with hyperadrenocorticotropism and hypercortisolemia, DHEA and DHEAS levels usually are not elevated. Nevertheless, ACTH and CRH might have a permissive role in the modulation of adrenal androgen secretion (Saenger & DiMartinoNardi, 2001). An increase of a central androgenstimulating proopiomelanocortin-derived hormone might be the primum movens of premature adrenarche (Battaglia et al., 2002). Increased sensitivity of the sexual hair follicles to androgens also has been suggested as a mechanism because in some patients, premature pubarche is associated with normal androgen levels (Guven et al., 2005; Ibanez et al., 2000). This phenomenon might account for the increased prevalence of premature adrenarche among Black children (Banerjee et al., 1998). The association of premature adrenarche with prematurity and intrauterine growth retardation suggests that premature adrenarche might be a component of a fetal or neonatal programming event (Auchus & Rainey, 2004). CLINICAL MANIFESTATIONS The frequency of premature adrenarche increases with age between 3 and 8 years of age in girls and between 3 and 9 years of age in boys, although cases have been reported as early as 5 weeks of age (Leung, 1989). Dark, coarse, and often curly hair is the rst clinical sign. The hair is limited initially to the labia majora in girls or to the root of the penis in boys and then

extends gradually into the pubic region (Figure 1). The amount and thickness of the hair might progress very slowly or not at all. Axillary hair, increased body odor, oily skin, and acne also might be noted (Ghizzoni & Milani, 2000; Ibanez et al., 2000). Acanthosis nigricans is more common in patients with premature adrenarche (DiMartino-Nardi, 2000). Hirsutism, deepening of the voice, clitoral enlargement, breast development, phallic or testicular enlargement, and other evidence of virilization or precocious puberty characteristically are absent. A transient acceleration of growth is common, but nal height usually is not affected (Battaglia et al., 2002; Ghizzoni & Milani, 2000). The onset of puberty usually occurs at the normal age (Battaglia et al.; Ibanez et al., 2000). DIFFERENTIAL DIAGNOSIS Premature adrenarche is a diagnosis of exclusion. The differential diagnosis of premature development of pubic hair is shown in the Table. Pubic hair of infancy presumably is due to transiently elevated androgen levels in the rst few months of life and increased sensitivity of sexual hair follicles to androgens (Leung, Hedge, & Stephure, 2005; Nebesio & Eugster, 2006). Shortly after birth, a transient surge of gonadotropins occurs and leads to a sharp increase in testosterone levels, which peaks at 1 to
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TABLE. Differential diagnosis of premature development of pubic hair

Condition Characteristics

Pubic hair of infancy

Pubic hair usually occurs in an atypical location such as scrotum in boys and mons pubis in girls; the growth of pubic hair is slowly progressive in the rst few months of life, remains stationary for a few months, and then might regress Premature adrenarche Isolated development of pubic hair without the appearance of other signs of sexual maturation; the onset of puberty is normal Precocious puberty Concomitant appearance of pubic hair with breast development in girls or with testicular enlargement in boys Virilizing tumors Acne, clitoral or phallic enlargement, hirsutism, markedly accelerated linear growth, and deepening of the voice at the same time or shortly after the onset of pubic hair development Late-onset congenital In addition to premature development of sexual hair, hirsutism adrenal hyperplasia and menstrual irregularities are usually present; in the male, the testes usually remain infantile but other secondary sexual characteristics are advanced; a positive family history is suggestive Iatrogenic A history of androgen exposure will give a clue to the diagnosis

cystic ovaries (DiMartino-Nardi, 2000). In some girls, premature adrenarche may be a forerunner of syndrome X (obesity, hypertension, insulin resistance, type 2 diabetes, and dyslipidemia) (Ibanez et al., 2000; Saenger & DiMartino-Nardi, 2001). Affected patients are at increased risk for early atherosclerotic cardiovascular disease (Saenger & DiMartinoNardi). In contrast, premature adrenarche in boys is not associated with an increased incidence of endocrine or metabolic abnormalities (Dorn & Rotenstein, 2004; Ibanez et al.). DIAGNOSTIC STUDIES Serum concentrations of DHEA, DHEAS, androstenedione, and testosterone and urinary 17-ketosteroids should be measured. In premature adrenarche, these levels are usually increased for chronologic age and are in the range of those found in early puberty (Battaglia et al., 2002). DHEAS levels, however, might exceed those of pubertal controls (Ibanez et al., 2000). A bone age x-ray should be preformed. In premature adrenarche, the bone age is usually within 2 standard deviations of chronologic age. Moderately elevated levels of serum androgen other than DHEAS, bone age advancement, or signs of atypical premature pubarche such as cystic acne or signs of systemic virilization indicate the need for an ACTH test to rule out congenital adrenal hyperplasia (Ibanez et al., 2000). An excessive increase in serum 17-hydroxyprogesterone level to 45 nmol/L after an ACTH stimulation test suggests late-onset congenital adrenal hyperplasia (Battaglia et al., 2002). Marked elevation of serum androgen levels and advanced bone age suggest the possibility of an adrenocortical or gonadal tumor. A patient with an androgen-producing adrenocortical tumor does not respond to ACTH stimulation or dexamethasone suppression, whereas a patient with congenital adrenal hyperplasia does respond. Adrenal
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3 months of age (Leung et al.). Thereafter, the gonadotropin levels fall, and by 6 months of age, serum levels of testosterone decrease to low prepubertal levels. In pubic hair of infancy, pubic hair usually occurs in an atypical location such as the scrotum in boys and the mons pubis in girls (Leung et al.; Nebesio & Eugster). The growth of the pubic hair is slowly progressive in the rst few months of life, remains stationary for a few more months, and then might regress. Precocious puberty can be differentiated by the concomitant appearance of pubic hair with breast development in girls or with testicular enlargement in boys. Premature adrenarche is extremely difcult, if not impossible, to differentiate from the early stage of constitutional precocious puberty. Sexual hair might be the rst sign of virilization due to an adrenocortical or gonadal tumor. In these conditions, other evidence of excessive androgen secretion such as acne, clitoral or phallic enlargement, hirsutism, increased muscle mass, markedly accelerated linear growth, and deepening of the voice usually appear at the same time or shortly after the onset of
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pubic hair development. In boys with an adrenocortical tumor, the testicular size is usually small, whereas the reverse is true for boys with a testicular tumor. Exogenous androgen can cause development of sexual hair as well as other signs of virilization. Obtaining a careful history about drug exposure is important. Congenital adrenal hyperplasia, usually resulting from 21-hydroxylase deciency, classically produces prenatal virilization in females but can, in a late-onset attenuated form, present with premature development of sexual hair, hirsutism, and menstrual irregularities. In the male, the testes usually remain infantile, but other secondary sexual characteristics are advanced. A positive family history of congenital adrenal hyperplasia is suggestive. COMPLICATIONS Girls with premature adrenarche have a higher incidence of polycystic ovary syndrome later in life (Andiran et al., 2005; Auchus & Rainey, 2004; Ibanez et al., 2002). Polycystic ovary syndrome is characterized by menstrual irregularities, obesity, acne, hirsutism, and poly-

Marked elevation of serum androgen levels and advanced bone age suggest the possibility of an adrenocortical or gonadal tumor.

computed tomography or ultrasonography should be performed if signicant virilization occurs and ACTH stimulation does not reveal congenital adrenal hyperplasia (Rodriguez & Pescovitz, 2003). Pelvic ultrasonography should be performed if polycystic ovary syndrome is suspected. The presence of an enlarged ovary and multiple small follicles scattered around an echogenic stroma establishes the diagnosis (Battaglia et al., 2002). Color Doppler ow measurements might reveal signicant vascular changes within the intra-ovarian vessels in patients with polycystic ovary syndrome (Battaglia et al.). Serum glucose, insulin, cholesterol, and triglyceride levels should be measured if syndrome X is suspected. MANAGEMENT Education and reassurance of the patient and family as well as psychological/emotional support for the child and family are essential to the clinical management of such patients. The parents and child should be reassured that, in most cases, premature adrenarche is a benign condition and that the child will develop normally. Continued observation and periodic re-evaluation are necessary because premature adrenarche might be the rst sign of precocious puberty. In some girls, premature adrenarche might be a forerunner of polycystic ovary syndrome or syndrome X. Girls with higher body mass index warrant particularly close follow-up (Miller, Emans, & Kohane, 1996). Early identication of these patients can allow early treatment of the appropriate condi-

tions with reduction in risk for early cardiovascular disease. REFERENCES

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