Pubertad Precoz

Julio 2008

 

 

Precocious Puberty in Girls

 

Se define Pubertad precoz como desarrollo puberal que ocurre bajo los límites de edad establecidos para el inicio normal de pubertad. Se considera pubertad precoz en niñas si el inicio de los caracteres sexuales secundarios ocurre antes de los 8 años de edad.

 

Precocious puberty is more common in girls than in boys. This disparity is explained by the large number of girls with central idiopathic precocity, a condition that is unusual in boys. Girls between 6 and 8 years of age may also show signs of puberty but it can be a benign, slowly progressing form that requires no intervention. The age of pubertal onset may also be advanced by obesity.  Central (gonadotropin-releasing hormone [GnRH]-dependent) precocious puberty involves activation of the hypothalamic GnRH pulse generator, an increase in gonadotropin secretion, and a resultant increase in the production of sex steroids . Consequently, the sequence of hormonal and physical events in central precocious puberty is identical to the progression of normal puberty.

 

Causes of Precocious Pubertal Development.

 

Central precocious puberty in girls is generally idiopathic but may be secondary to a demonstrable central nervous system (CNS) abnormality that disrupts the prepubertal restraint on the GnRH pulse generator. Such CNS abnormalities may include, but are not limited to, hypothalamic hamartomas, CNS tumors, cranial irradiation, hydrocephalus, and trauma. Peripheral precocious puberty (GnRH-independent) occurs independent of gonadotropin secretion. In girls, peripheral precocious puberty can be caused by ovarian or adrenal tumors, ovarian cysts, congenital adrenal hyperplasia, McCune-Albright syndrome, or exogenous estrogen. McCune-Albright syndrome is a triad consisting of irregular café-au-lait lesions, polyostotic fibrous dysplasia, and GnRH-independent precocious puberty. It is caused by an activating mutation in the gene that encodes the alfa-subunit of Gs, the G-protein that stimulates adenyl cyclase. Consequently, endocrine cells with this mutation have autonomous hyperfunction and secrete excess amounts of their respective hormones.

CAH, congenital adrenal hyperplasia; CNS, central nervous system; GnRH, gonadotropin-releasing hormone; HCG, human chorionic gonadotropin.

 

Symptoms and Signs

 

Normal sexual development and precocity in girls usually starts with breast development, followed by pubic hair growth and menarche, but the order may vary. The interval between breast development and menarche can range from 1–6 years but is usually about 2 years. Girls with ovarian cysts or tumors will generally have signs of estrogen excess such as breast development and possibly vaginal bleeding. Adrenal tumors or congenital adrenal hyperplasia will present with signs of adrenarche (ie, pubic hair, axillary hair, acne, and/or increased body odor). Children with precocious puberty usually have accelerated growth and may appear tall during childhood. However, because skeletal maturation (bone age) advances at a more rapid rate than linear growth, final adult stature may be compromised.

 

Laboratory Findings

 

One of the first steps in evaluating a child with early pubertal development is obtaining a radiograph of the left hand and wrist to determine skeletal maturity (bone age). If the bone age is advanced, further evaluation is typically warranted. In central precocious puberty, the basal serum concentrations of FSH and LH may still be in the prepubertal range. Thus documentation of the maturity of the hypothalamic-pituitary axis depends on demonstrating a pubertal LH response after stimulation with a GnRH agonist. In peripheral precocious puberty, basal serum FSH and LH are low, and the LH response to GnRH stimulation is suppressed as a result of feedback inhibition of the hypothalamic-pituitary axis by the autonomously secreted gonadal steroids (see Figure 30–1). In girls who have an ovarian cyst or tumor, estradiol levels will be markedly elevated. In girls who present with signs of adrenarche and an advanced bone age, androgen levels and possible adrenal intermediate metabolites (such as 17-hydroxyprogesterone) should be measured.

 

Imaging

 

Once the diagnosis of central precocious puberty is made, an MRI of the brain should be done to evaluate for CNS lesions. It is unlikely that an abnormality will be found in girls between 6 and 8 years of age, so the need for an MRI in this age group should be individually assessed. In girls whose labs suggest peripheral precocious puberty, an ultrasound of the ovaries and/or adrenal gland should be considered.

 

Benign Variants of Precocious Puberty

 

Premature thelarche (benign early breast development) occurs most commonly between ages 12 and 36 months. It is often bilateral but may begin or remain as unilateral breast enlargement. In the absence of other signs of pubertal development (eg, accelerated growth rate or skeletal maturation, pubic hair, or vaginal mucosal maturation), no laboratory evaluation is necessary. Treatment consists of reassurance regarding the self-limited nature of this condition, but observation of the child at regular intervals (eg, twice a year) is also useful. Onset of thelarche after age 3 or in association with other signs of puberty requires more evaluation.

Premature adrenarche (benign early adrenal maturation) is manifested by gradual increase in pubic hair and body odor, and less commonly, axillary hair and acne. The average age at onset is 5–6 years. No increase in growth rate or skeletal maturation occurs, and no abnormal virilization (eg, clitoromegaly) is present. No treatment is required, though girls with premature adrenarche are at risk for developing polycystic ovarian syndrome later on during puberty.

 

Treatment

 

Girls with central precocious puberty can be treated with GnRH analogs, such as leuprolide. GnRH analogs downregulate pituitary GnRH receptors and thus decrease gonadotropin secretion. With treatment, physical changes of puberty regress or cease to progress, and linear growth slows down to a prepubertal rate. Projected final heights often increase as a result of slowing of skeletal maturation. Usually, GnRH analogs are given as a monthly depot intramuscular injection, and side effects are rare. After discontinuation of therapy, pubertal progression resumes, and in girls ovulation and pregnancy have been documented. Therapy is considered for both psychosocial and final height considerations. Treatment for peripheral precocious puberty is dependent on the underlying cause. In a girl who has an ovarian cyst, intervention is generally not necessary, as the cyst usually regresses spontaneously. For congenital adrenal hyperplasia, treatment with glucocorticoids would be initiated. Surgical resection is indicated for the rare adrenal or ovarian tumor.

 

In McCune-Albright syndrome, analogs of GnRH are not initially helpful. Therapy with antiestrogens (eg, tamoxifen) or agents that block estrogen synthesis (eg, ketoconazole or testolactone), or both, may be effective. Regardless of the cause of precocious puberty or the medical therapy selected, attention to the psychological needs of the patient and family is essential.

 

Referencias

  1. de Sanctis C et al: Pubertal development in patients with McCune-Albright syndrome or pseudohypoparathyroidism. J Pediatr Endocrinol Metab 2003;16(Suppl 2):293. [PMID: 12729407]

  2. Partsch CJ et al: Management and outcome of central precocious puberty. Clin Endocrinol (Oxf) 2002;56:129. [PMID: 11874402]

  3. Gillis D, Schenker J: The evolving story of female puberty. Gynecol Endocrinol 2002;16:163. [PMID: 12012628]