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Adolescent Gyn Series

Precocious Puberty

Kecha A. LynShue, MD; Selma Feldman Witchel, MD

Far from the simple visual diagnosis that it would seem, the evaluation of precocious puberty must determine whether the disorder is just a variation of normal development, progressive/nonprogressive, or gonadotropin-releasing hormone (GnRH)-dependent/-independent. Correct differentiation is essential, both to eliminate possible serious underlying disorders and to provide reassurance for the patient and her parents.

Puberty is the process of physical maturation, during which the individual becomes physiologically capable of reproduction. Because age at onset and duration of puberty vary, clinicians must be able to differentiate between normal and abnormal patterns of development. Traditionally, puberty has been considered premature in girls when breast or pubic hair development occurs before age 8 years and/or menarche before age 10 years. Today, data suggest that sexual maturation is occurring earlier than previously reported, with 50% of American girls attaining Tanner 2 breast development by age 9.5 to 9.7 years. Black girls tend to have earlier development than white girls, but age at menarche has not decreased significantly in either group.1

These newer data have prompted reconsideration of the age at which puberty is considered precocious in girls. However, inconsistent inclusion criteria, cross-sectional design, and methodology limit the usefulness of these studies.2-5 Thus, there is no conclusive evidence of a decrease in age at menarche over the past 30 years.6 More importantly, for a specific patient, clinical decision-making processes should focus on age at onset, family history, physical findings, rate of pubertal progression, and skeletal status rather than strict chronologic-age criteria.

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VARIATIONS OF NORMAL PUBERTY

Puberty is initiated by increased pulsatile secretion of GnRH, leading to increased pituitary production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The LH stimulates ovarian androstenedione synthesis, the major precursor for FSH-stimulated estradiol synthesis in the granulosa cell. For most girls, thelarche is the first sign of puberty, with subsequent pubarche. Menarche generally occurs 2 years after thelarche.

Isolated Menarche

Premature isolated menarche is rare. Vaginal bleeding can be caused by trauma, sexual abuse, infection, foreign body, tumors (eg, rhabdomyosarcoma, endodermal sinus), or exogenous estrogen exposure. Other considerations include McCune-Albright syndrome and hypothyroidism. Growth velocity and bone age are usually normal. However, long-term estrogen exposure will accelerate bone age, whereas hypothyroidism will delay it.

Premature Thelarche

Premature thelarche is a relatively common, benign, self-limiting condition characterized by breast development in the absence of other signs of sexual maturation. Typically, the breast development begins at age 9 to 15 months. Pubic and axillary hair are absent, and growth velocity is normal. On ultrasonography, the ovaries are usually small, but may contain follicular cysts. No medical treatment is required, and patients are observed to confirm the lack of pubertal progression. Parents can generally be reassured that the condition will resolve spontaneously.

Premature Adrenarche

Premature adrenarche is an early increase in adrenal androgen production, resulting in the early appearance of pubic and/or axillary hair without other sexual development. Bone age and growth velocity are usually normal, but may be slightly advanced—especially among overweight children. Premature adrenarche is often seen in association with obesity or central nervous system (CNS) lesions. Evidence is emerging that some girls with premature adrenarche may have an increased risk to develop polycystic ovary syndrome (PCOS) as adolescents or adults.7 Girls with PCOS have an increased risk to develop impaired glucose tolerance, type 2 diabetes mellitus, or the metabolic syndrome. When the androstenedione and dehydroepiandroesterone sulfate (DHEAS) concentrations are appropriate to stage of pubic hair development and skeletal maturation is within normal limits, the patient can generally be longitudinally followed and the parents may be reassured. Nevertheless, lifestyle modification should be encouraged for children with premature adrenarche because of its potential to decrease the risk to develop PCOS and its associated morbidities.

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PRECOCIOUS PUBERTY

Precocious puberty should be suspected if there is evidence of excessive hormone action—eg, early development of breast and pubic hair, acne, adult body odor, acceleration of linear growth, advanced bone age (Table).8Precocious puberty may be either central (complete, true, or GnRH-dependent) or peripheral (incomplete or GnRH-independent).

Table not available online

Table . Causes of Isosexual Precocious Puberty8

Gonadotropin-releasing Hormone-dependent

Central precocious puberty (CPP) occurs when there is premature activation of the hypothalamic-pituitary-gonadal axis associated with progressive pubertal development.9 Most cases are idiopathic. Central nervous system disorders such as CNS tumors may cause precocious puberty by interfering with neuronal pathways that inhibit GnRH secretion. Children with a history of congenital or acquired brain trauma may undergo precocious puberty by a similar mechanism, or hypothalamic hamartomas may secrete GnRH and/or tumor growth factor-α.10,11 These hamartomas may present at early ages with gelastic seizures, and are typically sessile lesions at the base of the brain near the tuber cinereum or mamillary bodies. Infections affecting the CNS (eg, encephalitis, tuberculosis) and structural anomalies (eg, suprasellar cysts, hydrocephalus) may also manifest as precocious puberty. Precocity may occur with neurofibromatosis type 1 in association with optic gliomas. A history of CNS radiation may also lead to sexual precocity.

The treatment of choice for GnRH-dependent precocious puberty is a GnRH agonist to induce down-regulation of GnRH receptors and decrease gonadotropin secretion. Agonists are available as daily injections or depot forms administered every 28 days. One study investigating adult outcomes for girls treated with a GnRH agonist reported normal reproductive health.12

Gonadotropin-releasing Hormone-independent

Peripheral precocious puberty is associated with sex-steroid secretion independent of gonadotropin secretion. Ovarian follicular cysts can secrete sufficient estrogen to cause breast development and vaginal withdrawal bleeding. Similarly, granulosa or thecal cell tumors also secrete estrogen, and may be palpable on examination.13 Exogenous estrogen from ingestion or external application may lead to precocity. Despite concern regarding high plasma concentrations of phytoestrogens from consumption of soy infant formula, no deleterious consequences have been confirmed.14 Untreated hypothyroidism can lead to sexual precocity. McCune-Albright syndrome manifests as a triad consisting of "café-au-lait" spots, fibrous dysplasia of long bones, and precocious puberty, but all three features are not required for diagnosis.15

The virilizing congenital adrenal hyperplasias (CAHs) are characterized by overproduction of adrenal androgens.16 The most common form, 21-hydroxylase deficiency, involves decreased cortisol synthesis, increased production of adrenocorticotropic hormone (ACTH), and increased adrenal androgen production. In the classical (severe) forms, virilization of the external genitalia may be present. Nonclassical CAH manifests with the early development of pubic hair, axillary odor, or acne. Associated features include accelerated linear growth velocity, elevated 17-hydroxyprogesterone (17-OHP) concentrations, and advanced bone age (Figure).17 Glucocorticoid replacement therapy is generally indicated for CAH.

Other possible causes of androgen excess include adrenal and ovarian tumors, which should be suspected in a virilized girl when DHEAS or testosterone concentrations are elevated (Figure). Exogenous sources such as anabolic steroids may also cause precocious puberty.

Figure not available online

Figure. Evaluation of precocious puberty.17

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DIAGNOSIS

A thorough medical history and complete physical examination often elucidate the etiology of sexual precocity. Differentiation of nonprogressive forms (eg, premature thelarche) from progressive forms (eg, GnRH-dependent precocious puberty) is crucial. The history should include age at onset of symptoms, rate of progression, and exogenous hormone exposures. The physician should ask whether:

• Breast development pre- ceded or followed pubic hair development
• Apocrine odor is sufficient to require deodorant
• The growth rate has suddenly accelerated in terms of frequent changes in clothing or shoe sizes
• There has been environmental exposure to endocrine disruptors (eg, pesticides, hair care products containing hormones, phthalic esters)18
• The child is experiencing acne or clitoromegaly.

Family history may reveal relatives with early puberty or ambiguous genitalia. A family history of infant death may suggest CAH. Accelerated growth velocity is often seen with CAH. Since the pubertal growth spurt generally occurs early in GnRH-dependent puberty, breast development accompanied by growth acceleration may indicate the diagnosis of GnRH-dependent precocious puberty.

Any examination should include Tanner staging. Staging for breast development should be assessed by inspection and palpation, as chest adiposity may be mistaken for true breast tissue. In early development, pubic hair is long and straight along the labia majora. As development proceeds, hair becomes darker and coarser, and begins to extend laterally to the medial thighs. The vaginal mucosa changes in response to increasing estrogen levels, becoming thicker and a duller pink in color (in contrast to the prepubertal bright red). Posterior labial fusion suggests prenatal androgen exposure. Girls with virilizing disorders such as CAH or androgen-secreting tumors may have clitoromegaly. Finally, it is essential to determine whether the stages of breast and pubic hair are concordant.

A thorough neurologic examination is important to exclude CNS lesions. Radiography indicating a significantly advanced bone age suggests a pathologic condition. Laboratory evaluation is based on history and physical findings, and may include FSH, LH, estradiol, 17-OHP, androstenedione, DHEAS, thyroid-stimulating hormone, and free thyroxine levels. Referral to a pediatric endocrinologist is warranted for definitive testing and treatment (Figure). Stimulation tests with ACTH or leuprolide/gonadorelin may be required to confirm or exclude CAH or precocious puberty, respectively. Although CNS lesions are rare in girls with CPP, magnetic resonance imaging is warranted whenever neurologic signs or symptoms are present. Pelvic ultrasonography may identify ovarian cysts or tumors, and can assess uterine size and endometrial wall thickness.

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CONCLUSION

Premature sexual development may be the initial manifestation of an underlying disorder. Rapid skeletal maturation attributable to early secretion of sex hormones may result in short adult stature. Finally, sexually precocious girls may encounter significant psychological problems. They may have difficulty identifying with their peers. Their older appearance may lead to premature participation in risky behaviors or place them at increased risk for sexual abuse. The major goals of treatment are to prevent further pubertal progression until appropriate for chronologic age, and improve the potential for adult height within the predicted genetic target range.

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Kecha A. LynShue, MD, is fellow, Pediatric Endocrinology; and Selma Feldman Witchel, MD, is associate professor, Pediatrics. Both are in the Division of Pediatric Endocrinology, Childrenês Hospital of Pittsburgh, University of Pittsburgh, Pa.

References

1. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics. 1997;99(4):505-512.
2. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999;104(4 pt 1):936-941.
3. Root AW. Sexual precocity: a historical perspective and update. Fetal Pediatr Pathol. 2005;24(1):39-62.
4. Styne DM. Puberty, obesity and ethnicity. Trends Endocrinol Metab. 2004;15(10):472-478.
5. Slyper AH. The pubertal timing controversy in the USA, and a review of possible causative factors for the advance in timing of onset of puberty. Clin Endocrinol (Oxf). 2006;65(1):1-8.
6. Lee PA, Guo SS, Kulin HE. Age of puberty: data from the United States of America. APMIS. 2001;109(2):81-88.
7. Witchel SF. Puberty and polycystic ovary syndrome. Mol Cell Endocrinol. 2006;254-255:146-153.
8. Witchel SF, Plant TM. Puberty: gonadarche and adrenarche. In: Strauss JF, Barbieri RL, eds. Yen and Jaffe's Reproductive Endocrinology. 5th ed. Philadelphia, Pa: Elsevier Saunders; 2004:493-535.
9. Partsch CJ, Heger S, Sippell WG. Management and outcome of central precocious puberty. Clin Endocrinol (Oxf). 2002;56(2):129-148.
10. Price RA, Lee PA, Albright AL, Ronnekleiv OK, Gutai JP. Treatment of sexual precocity by removal of a luteinizing hormone-releasing hormone secreting hamartoma. JAMA. 1984;251(17):2247-2249.
11. Jung H, Carmel P, Schwartz MS, et al. Some hypothalamic hamartomas contain transforming growth factor alpha, a puberty-inducing growth factor, but not luteinizing hormone-releasing hormone neurons. J Clin Endocrinol Metab. 1999;84(12):4695-4701.
12. Heger S, Muller M, Ranke M, et al. Long-term GnRH agonist treatment for female central precocious puberty does not impair reproductive function. Mol Cell Endocrinol. 2006;254-255:217-220.
13. de Silva KS, Kanumakala S, Grover SR, Chow CW, Warne GL. Ovarian lesions in children and adolescents®an 11-year review. J Pediatr Endocrinol Metab. 2004;17(7):951-957.
14. Giampietro PG, Bruno G, Furcolo G, et al. Soy protein formulas in children: no hormonal effects in long-term feeding. J Pediatr Endocrinol Metab. 2004;17(2):191-196.
15. Lumbroso S, Paris F, Sultan C; European Collaborative Study. Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome—a European Collaborative Study. J Clin Endocrinol Metab. 2004;89(5):2107-2113.
16. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet. 2005;365(9477):2125-2136.
17. Root AW. Precocious puberty. Pediatr Rev. 2000;21(1):10-19.
18. Tiwary CM. Premature sexual development in children following the use of estrogen- or placenta-containing hair products. Clin Pediatr (Phila). 1998;37(12):733-739.

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