Precocious Puberty

Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 68 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Measurement of sex hormone levels, as well as X-rays to evaluate skeletal maturity, are used to diagnose and characterize PP. Correcting the hormonal excess at its root cause can appropriately delay the onset of puberty. A primary goal of treatment is the preservation of normal height potential.

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Overview

Definition

  • Precocious puberty (PP) is the appearance of secondary sexual characteristics before the age of 8 in girls and 9 in boys. 
  • There are multiple definitions of PP.
  • Some guidelines specify the age as < 7 years in white girls and < 6 years in black girls.

Classification

  • Central precocious puberty (CPP)
    • Gonadotropin-dependent, also called true precocious puberty 
    • Inappropriate activation of the hypothalamic-pituitary-gonadal (HPG) axis  
    • Increased gonadotropin-releasing hormone (GnRH) secretion
  • Peripheral precocious puberty (PPP)
    • Gonadotropin-independent 
    • Isosexual or heterosexual (contrasexual) secondary sex characteristics appear without HPG activation.
  • Mixed: Peripheral precocious puberty induces the maturation of HPG and onset of central puberty.

Epidemiology

The prevalence of precocious puberty varies based on the race and ethnic makeup of the population.

  • More common in girls than boys
  • CPP is more common than PPP.
  • Patients with early central nervous system (CNS) disease have a higher incidence.

Etiology

Central precocious puberty

  • Idiopathic: 90% of girls, 30% of boys
  • Associated with a CNS abnormality:
    • 75% of boys
    • Hamartomas most common causative tumor
  • CNS irradiation
  • Genetic

Peripheral precocious puberty

Causes of isosexual precocious pubertyCauses of heterosexual precocious puberty
Girls
  • Ovarian tumors
  • Ovarian cysts
  • Feminizing adrenal tumors
  • Exogenous estrogens
  • McCune-Albright syndrome
  • Congenital adrenal hyperplasia
  • Adrenal tumors
  • Exogenous androgens
  • Glucocorticoid receptor defect
Boys
  • Congenital adrenal hyperplasia
  • Adrenal tumors
  • Exogenous androgens
  • Leydig cell tumors
  • Chorionic gonadotropin–producing tumors
  • Familial male precocious puberty
  • Feminizing adrenal tumors
  • Exogenous estrogens

Clinical Presentation

Presenting complaints

  • Precocious puberty is diagnosed in the outpatient clinic, often prompted by parental observation.
  • Parents note early pubertal changes (body odor, new hair growth, oily skin, changes in voice and behavior).
  • Patients present for evaluation because they are abnormally short in stature. 
  • Precocious puberty can be a difficult subject for patients and parents to discuss.
  • Physician tact and knowledge of culturally appropriate practices are essential.

History

Focused history looking for possible causes of PP:

  • CNS: infection, perinatal asphyxia, head trauma, neoplasms and radiation, personality changes, headaches, visual field defects 
  • Exposure to endocrine disruptors: cosmetic, dietary products, or medications that may contain estrogens or androgens
  • Family history: Strong family history in males may indicate familial male-limited PP.

Clinical features in central precocious puberty

  • Secondary sex characteristics are isosexual.
  • Early development of breast buds in girls and of testicles (volume ≥ 4 mL) in boys.
  • Puberty occurs with a normal sequence:
    • Girls: thelarche (breast buds) → pubarche (pubic hair) → menarche 
    • Boys: growth of testes and thinning of scrotum → pigmentation of scrotum and growth of penis → pubarche
  • Major growth restriction (< 5th percentile of height as adults) occurs in 30% of girls and a larger proportion of boys: Height, weight, and osseous maturation are advanced, while mental development is normal for chronological age.
  • 3 main patterns of pubertal progression:
    1. Rapid physical and osseous maturation with loss of linear growth (most common, especially in girls < 6 years old)
    2. Slowly progressive osseous maturation with preserved linear growth (commonly seen in girls > 6)
    3. Transient CPP (rarest form)
  • The Tanner growth charts for breasts and pubic hair in girls and for testes and pubic hair in boys may be used for staging puberty.
Table: Tanner staging in males and females
Tanner stageBreasts (female)Pubic hairGenitals (male)
IB1: No breast development; no palpable glandular tissueP1: No pubic hairG1: Pre-pubertal: testicular volume < 4 mL and small penis
IIB2: Breast bud; areola begins to widen; small area of glandular tissueP2: Labia majora or mons pubis: small amount of long, downy hairG2: Testicular volume > 4 mL; skin on scrotum thins, reddens and enlarges; penis unchanged
IIIB3: Breast tissue enlarges; glandular tissue extends beyond the borders of the areolaP3: Hair becomes darker and coarser, extends laterally over the symphysisG3: Penis begins to grow, testicular volume increases further
IVB4: Breast bud: elevation of glandular tissue in the areola area from other breast tissueP4: Coarse hair (adult-like), less extendedG4: Penis increases in length and circumference; testicular volume increases further; scrotum enlarges further and darkens
VB5: Fully developed breast; areola returns to the contour of the surrounding breastP5: Coarse hair (adult-like), extended to the groin and medial thighsG5: Adult size genitalia with a testicular volume 12.5–19 mL

Diagnosis

Physical exam

  • General
    • Measurement of height, weight, and growth velocity
    • Assess for growth arrest
    • Calculation of expected height based on mid parental height:
      • (Mother’s height + father’s height + 13 cm in boys or – 13 cm in girls) ÷ 2
      • Compare to measured height based on growth charts
  • Neurological exam: evaluate for evidence of CNS mass
    • Evaluation of visual fields
    • Early morning headaches
  • Cutaneous exam
    • Look for cafe-au-lait spots for McCune-Albright syndrome
    • Evaluate for hirsutism
    • Evaluate for acne at inappropriate age
  • Genital exam
    • Pubertal staging through Tanner stages for consonance with expected for age
      • Measurement of testicular volume for boys
      • Measurement of diameter of glandular breast tissue in girls
      • Evaluation of pubic hair coverage for both
    • Evaluate for signs of genitourinary tumors
      • Asymmetric testicles
      • Lower abdominal swelling
      • Abdominal discomfort

Lab testing

  • Initial lab testing to differentiate CPP from PPP: serum levels of luteinizing hormone (LH), testosterone, and estrogen 
    • LH levels greater than 0.2–0.3 mIU/mL are suggestive of CPP.
      • Most boys with CPP have elevated serum testosterone levels at presentation.
      • Most girls with CPP have undetectable serum estrogen in the early stages of sexual precocity.
    • LH levels < 0.2 mlU/mL suggest PPP (very elevated estradiol is suggestive of tumor secretion).
  • GnRH stimulation test to confirm diagnosis 
    • Pubertal LH levels (peak > 5 IU/L) after intravenous administration of GnRH or GnRH agonists (leuprolide)
    • LH levels higher than peak after GnRH stimulus are suggestive of CPP.
    • Diagnosis of PPP is confirmed with pubertal levels of sex steroids but prepubertal levels of LH and FSH that do not increase following stimulation by GnRH or GnRH agonists.
  • Etiologic testing in PPP includes the following:
    • Dehydroepiandrosterone sulfate (DHEA-S) is usually elevated with premature pubarche.
    • 17-alpha progesterone is elevated in 21-hydroxylase deficiency (non-classic congenital adrenal hyperplasia), which is the cause in 3%–6% of patients with precocious pubarche (adrenarche). 
    • Human chorionic gonadotropin (HCG) is elevated in patients with HCG tumors.
    • Thyroid tests if suspected as the cause of PPP

Imaging

  • Bone X-ray:
    • Helpful diagnostic tool
    • In patients with sexual precocity, bone age is more advanced than chronological age by ≥ 2 years.
  • Pelvic ultrasound may show enlarged ovaries and uterus.
  • Brain magnetic resonance imaging (MRI):
    • Indicated in all boys with sexual precocity and girls with sexual precocity who have rapid breast development or estradiol levels > 30 pg/mL or who are < 6 years of age
    • May show pituitary growth to pubertal size
    • Helps exclude other pathology

Management

Goals

  • Help patients reach their genetic height potential.
  • Alleviate the psychosocial impact of early pubertal development.

Central precocious puberty

  • Idiopathic
    • Decision to treat with GnRH agonists is individualized based on the patient’s age, speed of puberty progression, and family coping.
    • In those treated with GnRH agonists, patients are closely monitored for response to therapy every 46 months.
  • Due to CNS lesion
    • Surgical resection of brain tumor 
    • ± brain radiation
    • Hamartomas may not require resection.

Peripheral precocious puberty

Directed at the cause, such as:

  • Surgical removal of secretory tumors (e.g., Leydig cell tumors)
  • Glucocorticoids in cases of adrenal hypersecretion (e.g., congenital adrenal hyperplasia)
  • Identification and removal of sources of exogenous sex steroids

References

  1. Lobo, R. A. (2017). Primary and secondary amenorrhea and precocious puberty: Etiology, diagnostic evaluation, management. In R. A. Lobo MD, D. M. Gershenson MD, G. M. Lentz MD & F. A. Valea MD (Eds.), Comprehensive gynecology (pp. 82-852.e3). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323322874000387
  2. Garibaldi, L. R., & Chemaitilly, W. (2020). Disorders of pubertal development. In R. M. Kliegman MD, J. W. St Geme MD, N. J. Blum MD, Shah, Samir S., MD,MSCE, Tasker, Robert C., MBBS,MD & Wilson, Karen M., MD,MPH (Eds.), Nelson textbook of pediatrics (pp. 289-2912.e1). https://www.clinicalkey.es/#!/content/3-s2.0-B9780323529501005782

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