Sexual precocity is defined as the appearance of secondary sexual characteristics before the age of 8 years in girls and before the age of 9 years in boys. Recent data suggest that these ages are less than two standard deviations from the mean. Still, the ramifications of misdiagnosis are great and, at present, breast or pubic hair development before age 8 or menarche before age 10 warrants an evaluation in girls. Testicular enlargement or pubic hair development before age 9 in boys warrants similar investigation. While the appearance of all secondary sex characteristics results from increased sex steroid production, the underlying etiology of elevated sex hormone production and activity may be increased gonadotropin secretion or intrinsic disease of the adrenal, ovary or testis (Table 28.1). Complete or true sexual precocity is used to describe precocious puberty resulting from elevated pituitary gonadotropins. Incomplete or peripheral sexual precocity refers to precocious puberty resulting from primary diseases of the gonads or adrenals. Early sexual development that is consistent with the genetic and gonadal sex of the individual is isosexual precocity. Heterosexual or contrasexual precocity indicates precocious puberty associated with feminization of a male or virilization of a female.
Although more than half the cases of isosexual precocious puberty simply represent the early end of the normal developmental spectrum, all children with sexual precocity should be evaluated. There are several reasons for this recommendation. First, some children may have a serious disorder associated with precocious puberty. Second, regardless of the etiology, sexual development that occurs before age 6–7 years can be associated with short stature in adulthood if left untreated. An X-ray of the left wrist to evaluate bone age can be used to determine when to initiate and stop chosen treatments for precocious puberty and to follow treatment efficacy. Finally, sexual precocity is not accompanied by advanced psychosexual maturation. To this point, young girls with precocious puberty appear to be at significant risk for sexual abuse. Ovulation and conception are possible and pregnancies in girls as young as 5 years of age have occurred as the result of such abuse. Appropriate therapy and support are necessary to prevent the potential long-term consequences of sexual precocity.
True or complete precocious puberty
True sexual precocity results from early maturation of the hypothalamic–pituitary–gonadal (HPG) axis. Measurements of serum gonadotropins and sex steroid concentrations will be in the normal postpubertal range. Gonadotropin pulsatility will have characteristics and feedback regulation similar to those found in the adult. The physical characteristics of puberty appear prematurely, but in the proper chronologic order. One half of cases of true sexual precocity arise from premature activation of the HPG axis (Table 28.2).
The remaining cases of complete isosexual precocity are caused by central nervous system (CNS) lesions. These lesions include neo- plasms, trauma, hydrocephalus, postinfectious encephalitis, congenital brain defects, tuberous sclerosis and neurofibromatosis type 1. Most lesions are located in, or near, the posterior hypothalamus. The most commonly identified neoplasms are astrocytomas, ependymomas and craniopharyngiomas. Hamartomas of the tuber cinereum account for one in six cases of isosexual precocious puberty in girls and half of the cases in boys. Hamartomas are congenital malformations that contain fibre bundles, glial cells and gonadotropin-releasing hormone (GnRH)-secreting neurons.
Although a rare cause of precocious puberty, girls with severe primary hypothyroidism can develop hyperprolactinemia, associated galactorrhea and true precocious puberty. These girls have a primary defect in the thyroid gland and very high thyroid-stimulating hormone (TSH) levels in response to low thyroid hormone secretion. They also have elevated circulating gonadotropins. The development of precocious puberty in girls with primary hypothyroidism may be the result of gonadotropin stimulation of the ovary, or from cross-activation of the follicle-stimulating hormone (FSH) receptor by the pathologically high TSH. In the face of low thyroid hormone secretion, hypothalamic thyrotropin-releasing hormone (TRH) production rises. TRH is a potent stimulator of prolactin secretion by pituitary lactotrophs (Chapter 32); hyperprolactinemia and galactorrhea result.
Occasionally, the development of true sexual precocity will follow the correction of a long-standing virilizing condition in girls. This may occur with treatment of congenital adrenal hyperplasia (CAH). Correction of excess androgen production releases the hypothalamus from androgen-associated negative feedback. This permits GnRH secretion and gonadotropin stimulation of the ovary. The timing of this stimulation may be inappropriate and, in a young girl, lead to complete precocious isosexual development.
Treatment of true precocious puberty involves recognition and correction of underlying CNS lesions if etiologic. Additional therapy may be required, including suppression of the HPG axis with a GnRH agonist or antagonist. GnRH agonists are long-acting analogs of GnRH that occupy its receptors for long periods of time. Prolonged receptor occupation removes the GnRH pulsatility required for appropriate gonadotropin release from the pituitary. GnRH antagonists occupy and block GnRH receptors and cause immediate cessation of GnRH pulsatility. Both are effective in protecting adult height and avoiding many psychosexual issues surrounding untreated precocious puberty.
Incomplete isosexual precocity
Incomplete isosexual precocity is caused by ovarian or adrenal secretion of estrogen in girls and testicular or adrenal secretion of androgen in boys. In girls, the most common cause of GnRH-independent precocious puberty is the presence of functionally autonomous ovarian cysts. Small (<1 cm) follicles occur frequently in the prepubertal ovary but they rarely secrete significant amounts of estrogen. However, autonomous secretion of estradiol by the granulosa cells contained in the cyst wall can occur in larger cysts, and serum estradiol concentrations appear to correlate directly with cyst size. Progestin therapy can reduce the size of these cysts and prevent their recurrence.
Solid stromal cell tumors of the ovary are a rare cause of GnRH-independent precocious puberty in girls. When compared with functional cysts of the ovary, juvenile granulosa or theca cell tumors secrete very large amounts of estrogen, often resulting in the rapid development of sexual characteristics.
Two inherited syndromes, Peutz–Jeghers and McCune–Albright, are associated with isosexual precocious puberty. Peutz–Jeghers syndrome is defined by the appearance of mucocutaneous pigmentation and gastrointestinal polyposis, but may also include gonadal sex cord tumors. McCune–Albright syndrome is characterized by hyperpigmented café-au-lait spots on the skin, progressive polyostotic fibrous dysplasia of the bones and GnRH-independent sexual precocity. Hyperplasia or adenomas of multiple endocrine glands may also occur.
McCune–Albright syndrome is caused by activating mutations in a signal transduction protein linked to many of the peptide hormone receptors, the G-protein subunit, Gsα. These proteins are present in many cells and therefore many tissues can be affected; distribution may be patchy and unpredictable because mutations occur in postzygotic somatic cells. In girls with McCune–Albright syndrome and ovarian involvement, sexual precocity occurs because of estrogen secretion from luteinized follicular cysts and treatment involves interruption of estrogen production. CNS involvement is unlikely and patients with McCune–Albright syndrome can progress normally through GnRH-dependent puberty.
Incomplete isosexual precocious puberty is rare in boys. It is always caused by excess androgen exposure. Adrenal sources of androgen exposure include CAH and adrenal adenomas or cancers. Most virilizing adrenal tumors in children secrete excess amounts of dehydroepiandrosterone sulfate (DHEA-S). The DHEA-S, in turn, is converted to more potent androgens (Chapter 2). Testicular sources of androgen excess include Leydig cell tumors. These rare tumors of the testis produce testosterone.
Iatrogenic sexual precocity
Breast development has been reported in girls and boys after exposure to exogenous estrogens found in tonics, lotions, creams and estrogencontaminated meat. Virilization of boys and girls has been associated with exposure to androgenic steroid preparations.
Virilizing precocious puberty in girls
Most girls with contrasexual precocious puberty will develop pubic hair or hirsutism. The most common cause is CAH. CAH is associated with multiple defects in the steroid synthetic pathway. Mild alterations in adrenal 21-hydroxylase are present in 0.1–1.0% of the population. These alterations may not manifest themselves as early as those of classical CAH; mild deficiencies are associated with late virilization, premature adrenarche, polycystic ovarian disease and postpubertal oligoamenorrhea. Diagnosis of this disorder rests on the presence of mild baseline elevations in 17-hydroxyprogesterone, the steroid precursor metabolized by 21-hydroxylase. Some patients with CAH will be discovered only after provocative testing, characterized by the exaggerated release of 17-hydroxyprogesterone to adrenocorticotropic hormone (ACTH) stimulation. Deficiencies in 11β ciency or cocious puberty in girls, but occur rarely.
Virilizing adrenal tumors that occur in young girls are very aggressive and usually fatal if malignant. Ovarian Leydig cell and Sertoli cell tumors are the most common virilizing neoplasms in women. They are a rare cause of virilizing precocious puberty.
Feminizing precocious puberty in boys Contrasexual precocity is much less common in boys than in girls. Boys with feminizing precocious puberty will exhibit gynecomastia and accelerated linear bone growth. The presence of prepubertal-size testes on examination strongly suggests an adrenal or testicular source for the estrogen. One rare cause of prepubertal feminization is extraglandular aromatization of androstenedione. Gynecomastia has occasionally been seen with CAH in boys. Feminizing testicular tumors have been reported in boys with Peutz–Jeghers syndrome.