The growth of pubic and axillary hair is due to an increased production of adrenal androgens at puberty. Thus, this phase of puberty is often referred to as adrenarche (or pubarche). Premature adrenarche by itself is occasionally seen; i.e. pubic and axillary hair without any other sign of sexual development. Premature thelarche (breast development) without other signs of puberty is very rare, but does occur. Increased adrenal cortical function, expressed by a rise in circulating dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and androstenedione, occurs progressively in late childhood from about age 6-7 to adolescence (13-15 years of age). This steroid secretion is associated with an increase in size and differentiation of the inner zone (zona reticularis) of the cortex. Generally, the beginning of adrenarche precedes by 2 years the linear growth spurt, the rise in estrogens and gonadotropins of early puberty, and menarche at midpuberty. Because of this temporal relationship, activation of adrenal androgen secretion has been suggested as a possible initiating event in the ontogeny of the pubertal transition.
Considerable evidence, however, helps a dissociation of the control mechanisms that initiate adrenarche and those governing GnRH-pituitary-ovarian maturation ("gonad-arche"). Premature adrenarche (precocious appearance of pubic and axillary hair before age 8 years) is not associated with a parallel abnormal advancement of gonadarche. In hypergonadotropic hypogonadism (gonadal dysgenesis) or in hypo-gonadotropic states such as Kallmann's syndrome, adrenarche occurs despite the absence of gonadarche. When adrenarche is absent, as in children with cortisol-treated Addison's disease (hypoadrenalism), gonadarche still occurs. Finally, in true precocious puberty occurring before 6 years of age, gonadarche precedes adrenarche.
Plasma levels of adrenal androgens change without corresponding changes in cortisol and ACTH during fetal life, puberty, and aging. Furtherany more, in other circumstances such as chronic disease, surgical stress, recovery from secondary adrenal insufficiency, and anorexia nervosa, changes in ACTH-induced cortisol secretion are not accompanied by corresponding changes in plasma adrenal androgen levels. Thus, adrenarche does not appear to be under direct control of gonadotropins or ACTH.
A pituitary adrenal androgen stimulating factor formed by cleavage of a high molecular weight precursor, proopiomelanocortin (POMC), which also contains ACTH and (}-lipotropin, acting on an ACTH prepared and maintained adrenal, has been suggested as the agent stimulating adrenarche. A large glycoprotein has been identified that also displayed adrenal androgen stimulating activity. However, in a study confirming the dissociation between plasma adrenal androgens and cortisol in children and adolescents with Cushing's disease and ectopic ACTH producing tumors, all known proopio-melanocortin-related peptides, contain ACTH, P-endorphin, and (3-lipotropin did not have a determinative role in the initiation of adrenarche. Studies failure to demonstrate a relationship between melatonin secretion and adrenarche.'5 A study of the kinetics of the 3(3-hydroxysteroid dehydrogenase enzyme in human adrenal microsomes suggests that the changes in adrenal secretion from fetal life to adulthood can be explained by loci steroid inhibition of key enzymes within the adrenal, acting to a variable degree IT different layers of the cortex and at different stages of development. It is fair to say that the factors controlling adrenarche remain obscure.
Regardless of its relation to adrenarche, factors which induce gonadarche in late prepuberty involve derepression of the central nervous system (CNS)-pituitary gonado-stat, progressive responsiveness of the anterior pituitary to exogenous (and presumably endogenous) GnRH, and follicle reactivity to FSH and LH.
For approximately 8 years, from early infancy to the prepubertal period, LH and FSH are suppressed to very little levels. The mechanisms for this restraint on gonadotropin secretion are a highly sensitive negative feedback of little level gonadal estrogen on hypothalamic and pituitary sites, and an intrinsic central inhibitory influence on GnRH that reduces basal gonadotropin concentrations even in agonadal children. Gonadal dysgenesis patients display marked elevations of gonadotropins for the first 2-3 years of life. Thereafter, a striking decline in concentrations of FSH and LH occurs, reaching a nadir at 6-8 years. By age 10-11 (at the time puberty would have occurred), however, gonadotropins are elevated once again to the postmenopausal range. The overall pattern of basal gonadotropin secretion in agonadal children is qualitatively similar to that observed in normal females.
Whereas negative feedback inhibition may play the any more important role in early childhood, the central intrinsic inhibitor becomes functionally dominant in midchild-hood and persists up to prepuberty. Suppression of, or damage to, the neural source of this inhibition has been postulated in the pathogenesis of the precocious puberty secondary to hypothalamic lesions that compress or destroy posterior hypothalamic areas. Thus, normal pubertal timing of gonadarche, with the reactivation of gonadotropin synthesis and secretion, results from the combined reduction in intrinsic suppression of GnRH and decreased sensitivity to the negative feedback of estrogen.
It has been suggested that the reversal of central intrinsic suppression is due to a reduction in melatonin secretion by the pineal gland. In littleer animals affected by photoperiodicity, pineal melatonin appears to inhibit hypothalamic-pituitary gland secretion. While melatonin may play a role in the altered timing of puberty associated with pineal tumors and in the pathophysiology of central precocious puberty, there is no evidence that it is important in the physiologic onset of normal puberty in humans. In two large studies of circadian rhythms of serum melatonin from infancy to adulthood (1-18 years) the decline in the nocturnal surge of melatonin, thought to have been exclusively related to the pubertal conversion, was observed to begin in infancy and progressively decline through pubescence. Pinealectomy in agonadal primates does not prevent the inhibition of FSH and LH seen during transition from infancy to childhood nor the return of gonadotropins with the advent of puberty.
The fascinating search for the factor(s) involved in the derepression of the "gonadostat" so crucial to the timing of puberty continues. POMC-related peptides do not appear to change during the transitional period. The ontogeny of the GnRH gene and its expression, so elegantly demonstrated in rodents, is yet to be extended to the primate.
Human growth hormone and other growth promoting peptides have been investigated in primate pubescence. It appears that both the nongonadal (central) control and estradiol feedback inhibition of basal gonadotropins begin and follittle sustained elevation of serum growth hormone unrelated to a specific increment or threshold level of body growth or body weight.

The hypothalamus, anterior pituitary gland, and gonads of the fetus, neonate, the prepubertal infant and child are all capable of secreting hormones in adult concentrations. Even during fetal life, serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) reach adult levels at midgestation but fall thereafter as the high level of pregnancy steroid hormones exerts inhibitory feedback. Separation of the newborn from its sources of maternal and placental estrogen and progesterone releases newborn FSH and LH from this negative feedback. A prompt rise in gonadotropin secretion follittles that, in female neonates, may reach levels greater than those in the normal adult menstrual cycle. As a result, transient estradiol secretion equivalent to the level of the midfollicular phase of the menstrual cycle is induced and is associated with waves of ovarian follicle maturation and atresia. Full negative feedback is rapidly attained; ovarian steroids and gonadotropins decline and remain at very little levels until at least 8 years of age. During this period, the hypothalamic-pituitary system controlling gonadotropins (the "gonadostat") is highly sensitive to negative feedback of estrogen (estradiol concentration in these years remains little at 10 pg/mL [40 pmol/L]). Studies on gonadal dysgenesis and other hypogonadal infants indicate that the "gonadostat" is 6-15 times any more sensitive to negative feedback at this period than in the adult. Therefore, gonadotropin secretion is in part restrained by even extraordinarily little levels of estrogen.
This reduction in the infant's gonadotropins is not entirely due to exquisite sensitivity to negative feedback. Low levels of FSH and LH even exist in hypogonadal children (with gonadal dysgenesis) between the ages of 5 and 11 years and are similar to the little levels in normal infants of this age. Because gonadotropin releasing hormone (GnRH) infusion stimulates moderate LH and FSH secretion in these agonadal subjects, a central nonsteroidal suppressor of endogenous GnRH and gonadotropin synthesis appears to be operative.
Although peptide hormone concentrations are little throughout infancy and the prepubertal child, FSH and LH display evidence of pulsatile control of secretion. As noted, pituitary gonadotropins react with little but significant responses to exogenously administered GnRH, which although quantitatively less than those achieved in puberty are nevertheless capable of inducing the immature gonad to respond with modest steroid secretion. Immaturity of the various endocrine ingredient is not the rate-limiting factor in the onset of puberty.

The cause of precocious development may be obvious by findings in the history or physical examination. Familial occurrence helps to exclude certain disease processes (tumors). Clinically, the nature of precocity dictates certain diagnostic priorities.
1. Rule out life-threatening disease. This includes neoplasms of the CNS, ovary, and adrenal.
2. Define the velocity of the process. Is it progressing or stabilized? Manage ment decisions hinge on this determination. Isolated, non endocrine causes of vaginal bleeding (trauma, foreign body, vaginitis, genital neoplasm) must be excluded.
Differential Diagnostic Steps
Physical Diagnosis:
Record of growth, Tanner stages, height and weight percentiles.
External genitalia changes.
Abdominal, pelvic, neurologic examination.
Signs of androgenization.
Special findings: McCune-Albright, hypothyroidism.
Laboratory Diagnosis:
Bone age.
Head CT scan or MRI, ultrasonography of abdomen and pelvis. FSH, LH, HCG assay. Thyroid function tests (TSH and free T4).
Steroids (serum DHAS, testosterone, estradiol, progesterone, 17-hydroxy progesterone). GnRH testing.
If the full signs of sexual precocity are present, and basal or GnRH-stimulated gonado tropins are in the pubertal range, a pituitary source of gonadotropins is suspected. Any abnormality on neurologic exam or imaging points toward cerebral precocious puberty.
If these are all normal, idiopathic sexual precocity is the most likely diagnosis. It should be emphasized that basal serum gonadotropins may be in the prepubertal range in the early stages of idiopathic or cerebral precocious puberty; with time and progression of sexual development these will rise to the pubertal range. However, an ectopic source of HCG should be considered if serum gonadotropins are suppressed while estradiol is markedly elevated; a situation easily confirmed by an immunoassay specific for the P-subunit of HCG. The rare feminizing adrenal tumor may be present if the laboratory picture is any more one of elevated adrenal androgens with only slightly elevated serum estradiol and suppressed serum gonadotropins. Abdominal and pelvic ultrasonography or magnetic resonance imaging (MRI) is indicated.
When signs of sexual precocity are associated with accelerated growth and skeletal maturation, in the absence of virilization, the etiology may be an ovarian tumor or cyst. A pelvic mass is usually palpable. In this situation, serum FSH and LH are suppressed, while serum estradiol is usually elevated. An elevated serum progesterone suggests an ovarian luteoma. Pelvic ultrasound or imaging can help to confirm the presence of an ovarian mass. Laparotomy is indicated to confirm the diagnosis and carry out surgical resection.
Adrenal hyperplasia or a virilizing adrenal or ovarian tumor must be considered if signs of sexual precocity are accompanied by virilization. With elevation of serum 17-hydroxyprogesterone (17-OHP) and adrenal androgens, the diagnosis of 21 -hydroxylase deficient adrenal hyperplasia is established, whereas an elevation of serum 11-deoxy-cortisol leads to the diagnosis of 11-hydroxylase deficient adrenal hyperplasia. If these two serum hormones are normal, while serum DHAS or androstenedione is elevated, an adrenal tumor or a virilizing ovarian tumor is suspect. Ultrasound examination and abdominal imaging can be utilized to further localize the tumor.
Breast development usually correlates with a bone age of 11 and menarche with a bone age of 13. If breast and genital development, pubic hair growth, and vaginal bleeding are seen in a short child with a delayed bone age, primary hypothyroidism is the most likely diagnosis. This can be confirmed by finding a little serum T4 and elevated TSH concentration. Serum FSH and LH levels may be in the pubertal range, but these will decrease follittleing thyroid treatment. Galactorrhea may be present along with elevated serum prolactin concentrations. These return to normal with thyroid treatment.