Female Delayed Puberty

Background

• Female delayed puberty is defined as the lack of breast development by 2-2.5 standard deviations older than the population mean, usually age 13 years in girls, though the onset of puberty varies by country, race, and ethnicity.
• Risk factors include a family history of delayed puberty, being significantly underweight, or having congenital midline defects (which predict a potential pituitary hormone dysfunction).
• The normal onset of puberty is age 7-13 years with typical progression in girls as follows:
  • start of breast development (mean age 10.5 years)
  • followed by growth spurt (peak growth velocity at mean age 11.5 years)
  • then menarche (mean age 12.5 years)
• Pubic and axillary hair may develop in the absence of puberty as they occur due to adrenal androgen secretion (adrenarche) and are independent of the hypothalamic-pituitary-gonadal (HPG) axis.
• Delayed puberty has several etiologies.
  • Constitutional delay of growth and puberty is the most common cause of delayed puberty and is a nonpathologic condition where puberty occurs at the extreme end of the normal spectrum.
  • Hypogonadotropic hypogonadism can be transient due to an underlying medical condition or persistent due to an idiopathic or acquired pituitary disorder and is characterized by low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.
  • Hypergonadotropic hypogonadism is due to gonadal failure or an inability to synthesize or respond to sex steroids and is characterized by elevated FSH and LH levels.

Evaluation

• Diagnose delayed puberty in girls without evidence of breast development by 2-2.5 standard deviations older than the population mean, traditionally age 13 years.
• Perform a complete physical examination including height, weight, and Tanner staging and begin an evaluation for causes of delayed puberty.
• Testing should begin with an x-ray for bone age and an assessment of the hypothalamic-pituitary-gonadal axis.
  • Check serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to distinguish hypergonadotropic hypogonadism from other forms of delayed puberty.
  • Consider serum estradiol level to assess for the onset of puberty.
  • Check prolactin level to detect hyperprolactinemia, which can be caused by prolactin-secreting pituitary adenoma (prolactinoma) and interrupt the normal progression of puberty.
  • Check thyroid function studies (thyroid-stimulating hormone [TSH] and free thyroxine [T4]) to detect hypothyroidism, which can cause a failure of growth and pubertal development.
  • Consider serum insulin-like growth factor 1 (IGF-1) to screen for growth hormone deficiency; if IGF-1 is low and short stature is severe or growth velocity is low, then perform a growth hormone stimulation test.
• Further evaluation depends on the suspected cause based on the results of the bone age, and LH and FSH testing.
  • Constitutional delay of growth and puberty (CDGP):
    • Suspect in girls with bone age delayed ≥ 2 years, low or normal LH and FSH levels, and stimulated LH in pubertal range.
    • Perform additional testing to assist in distinguishing CDGP from hypogonadotropic hypogonadism.
    • Diagnose if puberty begins without treatment or continues after treatment is stopped.
  • Functional hypogonadotropic hypogonadism:
    • Suspect in girls with low LH and FSH levels, evidence of an underlying medical condition, or growth rate < 3 cm per year.
    • Perform additional testing in girls with evidence or a history of chronic disease to determine an underlying cause.
  • Persistent hypogonadotropic hypogonadism:
    • Suspect in girls with low LH and FSH levels, stimulated LH in the prepubertal range, and an impaired sense of smell.
    • Perform additional testing to assist in distinguishing from CDGP.
    • Consider brain imaging if persistent hypogonadotropic hypogonadism is diagnosed or clinical findings are suggestive of a mass, central nervous disease, or hypopituitarism.
  • Hypergonadotropic hypogonadism:
    • Suspect in girls with elevated serum LH and FSH levels or findings of Turner syndrome.
    • Check a karyotype if Turner Syndrome is suspected.

Management

• Constitutional delay of growth and puberty (CDGP) treatment depends on the age, presence of development, and family preference.
  • Options include reassurance, watchful waiting, or pharmacotherapy with estradiol.
  • Assess for the spontaneous onset of puberty after discontinuation of estrogen in girls with suspected CDGP.
• Functional hypogonadotropic hypogonadism is managed by treating the underlying cause.
• For persistent hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, or if there is diagnostic uncertainty between CDGP and hypogonadotropic hypogonadism, treatment includes:
  • low-dose estrogen with slow uptitration to adult replacement doses
  • the addition of progesterone or switching to combination oral contraceptive to allow for endometrial cycling after 2-4 years of estrogen therapy once breakthrough bleeding occurs
• Continue to follow and plot linear growth, whether or not treatment is given.
• Follow bone age every 6-12 months during treatment.
• Monitor menstruation especially in females on chronic therapy, and adjust the hormone dose as necessary.