Precocious puberty is onset of sexual maturation before the average age. Diagnosis is by comparison with population standards, x-rays of the left hand and wrist to assess skeletal maturation and check for accelerated bone growth, and measurement of serum levels of gonadotropins and gonadal and adrenal steroids. Treatment depends on the cause.
In girls, the first pubertal milestone is typically breast development (thelarche), followed soon after by appearance of pubic hair (pubarche) and axillary hair and later by the first menstrual period (menarche), which traditionally occurs 2 to 3 years after thelarche.
Статеве дозрівання — коли розвиваються жіночі статеві ознаки
Bars indicate normal ranges. |
In boys, the first pubertal milestone is typically testicular growth, followed by penile growth and appearance of pubic and axillary hair.
Статеве дозрівання — коли розвиваються чоловічі статеві ознаки
Bars indicate normal ranges. No mean is available for change in habitus. |
In both sexes, appearance of pubic and axillary hair is called adrenarche. Adrenarche may occur before gonadarche in about 10% of children (premature adrenarche). Although gonadarche and adrenarche may have overlapping signs, they are regulated independently.
The definition of precocious puberty has traditionally been before age 8 in girls or age 9 in boys. However, the current definition depends on reliable population standards for onset of puberty (ie, when pubertal milestones occur); because onset is occurring earlier in the United States, especially in females, these traditional standards are being reevaluated. Breast development is increasingly occurring at younger ages. This trend is mirroring the obesity epidemic, with a higher body mass index (> 85th percentile) associated with earlier thelarche.
Racial and ethnic differences may also play a role, for example, early breast changes are noted in a higher percentage of Black girls (23.4% by age 7, 42.9% by age 8) compared to White girls (10.4% by age 7, 18.3% by age 8) and Hispanic girls (14.9% by age 7, 30.9% by age 8) (1). The lower limit of normal puberty may be 7 years for White girls and 6 years for Black girls, but this remains controversial. The mean age for early breast development is about 9.5 to 10 years for White girls and 8.5 to 9 years for Black girls (range 8 to 13 years). The mean age for pubic hair growth is 9.5 years for Black girls and 10.5 years for White girls. However, the age of menarche has not lowered as drastically, with a mean decrease of only 3 months in the past 30 years (mean age 11.5 years in Black girls and 12.5 years in White girls). These findings imply that guidelines for evaluating disorders that cause precocious puberty can be interpreted more leniently if children are otherwise healthy and are projected to reach their full adult height potential.
Довідковий матеріал загального характеру
1. Biro FM, Galvez MP, Greenspan LC, et al. Pubertal assessment method and baseline characteristics in a mixed longitudinal study of girls. Pediatrics. 2010;126(3):e583-e590. doi:10.1542/peds.2009-3079
Classification of Precocious Puberty
Precocious puberty can be divided into 2 types:
Gonadotropin-releasing hormone (GnRH)–dependent (central precocious puberty)
GnRH-independent (peripheral sex hormone effects)
GnRH-dependent precocious puberty is more common overall and 5 to 10 times more frequent in girls. In GnRH-dependent precocious puberty, the hypothalamic-pituitary axis is activated, resulting in enlargement and maturation of the gonads, development of secondary sexual characteristics, and oogenesis or spermatogenesis.
GnRH-independent precocious puberty is much less common. Secondary sexual characteristics result from high circulating levels of estrogens or androgens, without activation of the hypothalamic-pituitary axis.
Precocious puberty may also be classified by whether gonadarche or adrenarche occurs. In girls, gonadarche includes breast development, change in body habitus, growth of the uterus, and eventually menarche. In boys, gonadarche includes testicular enlargement; phallic growth; the initial appearance of pubic, facial, and axillary hair; adult body odor; and facial skin oiliness or acne. Adrenarche for both girls and boys involves the development of body hair, body odor, and acne.
Incomplete or unsustained pubertal development is common, most often as isolated premature thelarche or adrenarche. Girls with premature thelarche typically display breast development during the first 2 years of life, but this change is not accompanied by pubertal hormone levels, menarche, advanced bone age on x-ray, androgen effects, or growth acceleration. Isolated premature adrenarche is likewise not associated with progressive pubertal development.
Children with premature adrenarche may have signs of adrenal androgen production (eg, pubic hair, acne, body odor) that progress slowly usually without acceleration of linear growth. Premature adrenarche may be associated with later development of polycystic ovary syndrome in adolescence.
Etiology of Precocious Puberty
ГнРГ-залежне передчасне статеве дозрівання
In most affected girls, a specific cause cannot be identified. In the absence of specific symptoms or signs of central nervous system disease, the probability of an intracranial anomaly depends on younger age of onset of puberty (< 6 years in girls) and sex of the child (more common among boys).
Overall, affected boys are more likely to have identifiable cranial pathology than girls (13% vs 2% in a study of 205 children) (1). Such lesions include intracranial tumors, especially of the hypothalamus or pineal gland region, including hamartomas, gliomas, germinomas, and adenomas.
Neurofibromatosis and a few other rare disorders have also been linked to precocious puberty.
GnRH-dependent precocious puberty can also arise from iatrogenic causes (eg, surgery, radiation, or chemotherapy for cancer).
A family history of GnRH-dependent precocious puberty is another risk factor. Mutations have been identified in several genes to date, but testing remains in its infancy.
ГнРГ-незалежне передчасне статеве дозрівання
The etiology of GnRH-independent precocious puberty depends on the predominant sex hormone effect (estrogenic or androgenic), and physical changes are often markedly discordant from normal pubertal development.
Estrogenic effects are most commonly caused by follicular ovarian cysts; other causes include granulosa-theca cell tumors and McCune-Albright syndrome (a triad of follicular cysts, polyostotic fibrous dysplasia, and café-au-lait spots).
Adrenal enzyme defects, specifically congenital adrenal hyperplasia, are the most common pathologic form of androgen excess in children of either sex.
Additional causes of GnRH-independent precocious puberty in boys include familial male gonadotropin-independent precocity (due to an activating mutation of the gene for luteinizing hormone [LH] receptors), testosterone-producing testicular tumors, rarely ectopic beta-human chorionic gonadotropin (beta-hCG) production resulting from certain tumors (due to activation of LH receptors in testes), and occasionally McCune-Albright syndrome.
Довідковий матеріал щодо етіології
1. Hansen AB, Renault CH, Wøjdemann D, et al: Neuroimaging in 205 consecutive Children Diagnosed with Central Precocious Puberty in Denmark. Pediatr Res 93(1):125-130, 2023. doi: 10.1038/s41390-022-02047-2
Symptoms and Signs of Precocious Puberty
Physical changes are typically those of normal puberty for a child of that sex, with the exception of age of onset.
In girls, breasts develop, and pubic hair, axillary hair, or both appear. Girls may begin to menstruate.
In boys, facial, axillary, and pubic hair appears and the penis grows, with or without enlargement of testes, depending on the etiology.
Body odor, acne, and behavior changes may develop in either sex.
Pubertal growth spurt is seen in both sexes (with early-mid puberty in females, mid-late puberty in males), but premature closure of the epiphyses results in short adult stature. Ovarian or testicular enlargement occurs in precocious puberty but is absent in isolated precocious adrenarche.
Diagnosis of Precocious Puberty
Bone age x-rays
Serum hormone measurement
Possibly pelvic ultrasonography and brain MRI
Diagnosis of precocious puberty is clinical. X-rays of the left hand and wrist are done to check for accelerated skeletal maturation as a result of sex hormone effect. Unless history and examination suggest an anomaly, no further evaluation is required for children with pubertal milestones that are within 1 year of population standards. Girls and boys with isolated premature adrenarche and girls with premature thelarche also do not require further evaluation as long as x-rays confirm that skeletal maturation is not accelerated.
When further evaluation is necessary, blood tests should be chosen according to the features present. For patients who have mainly androgen effects, the most useful initial tests include measurements of total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, and luteinizing hormone (LH); all should be measured using high-sensitivity assays designed for pediatric patients and preferably in the morning. Measurement of morning LH levels is the best initial biochemical test for the diagnosis of GnRH-dependent precocious puberty, with values > 0.2 to 0.3 mIU/L (> 0.2 to 0.3 units/L) considered pubertal (1), depending on the assay. For patients who have only estrogen effects, the most useful screens for girls include ultrasensitive LH and estradiol, and, for boys, LH, beta-human chorionic gonadotropin, and estradiol. Follicle-stimulating hormone (FSH) levels have more limited usefulness in differentiating children with GnRH-dependent precocious puberty from nonprogressive variants.
Pelvic and adrenal ultrasonography may be useful if any of the steroid levels are elevated. MRI of the brain may be done to rule out intracranial anomalies in females < 6 years of age, in males with GnRH-dependent precocious puberty, or in any child with GnRH-dependent precocious puberty who has central symptoms (eg, headaches, visual changes).
A GnRH stimulation test may be considered to confirm GnRH-dependent precocious puberty when initial tests are inconclusive in the setting of clinically progressive puberty. Previously, a 1-hour stimulation test with the GnRH agonist gonadorelin was used, but because gonadorelin is no longer available, other GnRH agonists such as leuprolide are used. GnRH stimulation tests can be done because a GnRH agonist has an initial stimulatory effort on gonadotropins. Leuprolide acetate subcutaneously is given and LH, FSH, testosterone (only in boys), and estradiol (only in girls) are measured at 0, 1, and 2 hours. At 24 hours post-leuprolide, estradiol may be measured to improve sensitivity of the test (considered pubertal if > 50 pg/mL [> 184 pmol/L]) (2).
In GnRH-dependent precocious puberty, gonadotropin responses are pubertal, with stimulated LH levels > 5.00 mIU/L (> 5 units/L) in response to leuprolide (1). In GnRH-independent precocious puberty, gonadotropin responses to leuprolide are prepubertal.
Genetic testing may be considered in familial cases of GnRH-dependent precocious puberty, but this remains controversial.
Довідкові матеріали щодо діагностики
1. Bangalore Krishna K, Fuqua JS, et al: Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium. Horm Res Paediatr 91(6):357-372, 2019. doi: 10.1159/000501336
2. Sathasivam A, Garibaldi L, Shapiro S, et al: Leuprolide stimulation testing for the evaluation of early female sexual maturation. Clin Endocrinol (Oxf) 73(3):375-381, 2010. doi: 10.1111/j.1365-2265.2010.03796.x
Treatment of Precocious Puberty
For GnRH-dependent precocious puberty, GnRH agonist therapy
For GnRH-independent precocious puberty, androgen or estrogen antagonist therapy
Rarely tumor excision
If pubertal milestones are within 1 year of population standards, reassurance and regular reexamination are sufficient. Treatment is not needed for premature adrenarche or thelarche, but regular reexamination is warranted to check for later development of precocious puberty.
ГнРГ-залежне передчасне статеве дозрівання
For GnRH-dependent precocious puberty, pituitary LH and FSH secretion can be suppressed with GnRH agonists. The decision to treat with GnRH agonists depends on the age of the patient, rate of pubertal progression, height velocity, and rate of skeletal maturation on bone age x-ray. GnRH agonists may be used to preserve adult height, with younger children (girls < 7 years of age and boys < 9 years of age) with more rapid progression of pubertal changes benefiting more, and to potentially relieve psychosocial stress (data are more limited to support the potential impact of this intervention). The decision to stop treatment should be individualized and should be around the age when peers are concurrently progressing through puberty.
Treatment regimens include leuprolide acetate injections (subcutaneous or IM), triptorelin injections (IM), or histrelin implants (changed annually). Responses to treatment must be monitored every 3 to 6 months and medication dosages modified accordingly, usually until age 11 years in girls and age 12 years in boys (1, 2).
In girls with McCune-Albright syndrome, aromatase inhibitors, such as letrozole and anastrozole, have been used with varying success to reduce estradiol.
ГнРГ-незалежне передчасне статеве дозрівання
If GnRH-independent precocious puberty in boys is due to familial male gonadotropin-independent precocity or McCune-Albright syndrome, androgen antagonists (eg, spironolactone) ameliorate the effects of excess androgen. The antifungal ketoconazole reduces testosterone in boys with familial male gonadotropin-independent precocity.
If GnRH-independent precocious puberty is due to a hormone-producing tumor (eg, granulosa-theca cell tumors in girls, testicular tumors in boys), the tumor should be excised. However, girls require extended follow-up to check for recurrence in the contralateral ovary (3, 4).
Довідкові матеріали щодо лікування
1. Krishna KB, Fuqua JS, Rogol AD, et al: Use of gonadotropin-releasing hormone analogs in children: Update by an international consortium. Horm Res Paediatr 91(6):357–372, 2019. doi: 10.1159/000501336
2. Kilberg MJ, Vogiatzi MG: Approach to the Patient: Central Precocious Puberty. J Clin Endocrinol Metab 108(8):2115-2123, 2023. doi: 10.1210/clinem/dgad081
3. Aguirre RS, Eugster EA: Central precocious puberty: From genetics to treatment. Best Pract Res Clin Endocrinol Metab 32(4):343–354, 2018. doi: 10.1016/j.beem.2018.05.008
4. Latronico AC, Brito VN, Carel J-C: Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol 4(3):265–274, 2016. doi: 10.1016/S2213-8587(15)00380-0
Ключові моменти
Precocious puberty is the onset of sexual maturation before the average age based on population standards.
Most commonly, secondary sexual characteristics develop prematurely because the hypothalamic-pituitary axis is activated (GnRH-dependent precocious puberty); often the cause is idiopathic, but some children have a central nervous system anomaly.
Less commonly, the cause is high circulating levels of estrogens or androgens (GnRH-independent precocious puberty) caused by congenital adrenal hyperplasia or various gonadal tumors.
Diagnosis is made by bone age x-rays and measurement of LH and testosterone (in boys), and estradiol (in girls).
Treat GnRH-dependent precocious puberty with the GnRH agonists leuprolide, triptorelin, or histrelin.
Treat GnRH-independent precocious puberty based on the cause, including giving androgen or estrogen antagonists and removing tumors.
