The remaining cases of complete isosexual precocity are caused by central nervous system (CNS) lesions. These lesions include neoplasms, 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.

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