Delayed Puberty

Posted by • February 2nd, 2012

The latest article in our Clinical Practice review series is, “Delayed Puberty.” Puberty is considered delayed when it has not yet occurred at an age that is 2 to 2.5 SD later than average (traditionally, 14 years in boys and 13 years in girls). Constitutional delay of growth and puberty (CDGP) is the most common cause. Management of CDGP is discussed.

Puberty leads to sexual maturation and reproductive capability. It requires an intact hypothalamic-pituitary-gonadal (HPG) axis and is heralded by the reemergence of gonadotropin-releasing hormone (GnRH) secretion from its relative quiescence during childhood. GnRH stimulates the secretion of luteinizing hormone and follicle-stimulating hormone (FSH), which then stimulate gonadal maturation and sex-steroid production. Much is known about components of the HPG axis, but the factors that trigger pubertal onset remain elusive. It is not understood why one boy begins puberty at the age of 10 years and another at the age of 14 years.

Clinical Pearls

How is delayed puberty defined?

Delayed puberty is defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SD later than the population mean (traditionally, the age of 14 years in boys and 13 years in girls). However, because of a downward trend in pubertal timing in the United States and other countries and differences in pubertal timing among racial and ethnic groups, some observers have advocated for updated definitions with younger age cutoffs for the general population or perhaps for particular countries or racial or ethnic groups. Development of pubic hair is usually not considered in the definition because pubarche may result from maturation of the adrenal glands (adrenarche), and the onset of pubic hair can be independent of HPG-axis activation.

What is the most common etiology of delayed puberty, and what is the differential diagnosis?

Delayed puberty usually represents an extreme of the normal spectrum of pubertal timing, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP). Although CDGP represents the single most common cause of delayed puberty in both sexes, it can be diagnosed only after underlying conditions have been ruled out. The differential diagnosis of CDGP can be divided into three main categories: hypergonadotropic hypogonadism (characterized by elevated levels of luteinizing hormone and FSH owing to the lack of negative feedback from the gonads), permanent hypogonadotropic hypogonadism (characterized by low levels of luteinizing hormone and FSH owing to hypothalamic or pituitary disorders), and transient hypogonadotropic hypogonadism (functional hypogonadotropic hypogonadism), in which pubertal delay is caused by delayed maturation of the HPG axis secondary to an underlying condition. The cause of CDGP is unknown, but it has a strong genetic basis. It has been estimated that 50 to 80% of variation in the timing of puberty in humans is due to genetic factors, and 50 to 75% of patients with CDGP have a family history of delayed puberty.

Morning Report Questions

Q: What is an appropriate initial evaluation in a patient presenting with delayed puberty?

A: The aim of initial evaluation is to rule out underlying disorders causing delayed puberty. A family history, including childhood growth patterns and age at pubertal onset of the parents, should be obtained. Patients and their parents should be questioned about a history or symptoms of chronic disease, with emphasis on specific disorders (e.g., celiac disease, thyroid disease, and anorexia) that may cause temporary delay of puberty (functional hypogonadotropic hypogonadism), as well as medication use, nutritional status, and psychosocial functioning. Delayed cognitive development associated with obesity or dysmorphic features may suggest an underlying genetic syndrome. Bilateral cryptorchidism or a small penis at birth and hyposmia or anosmia may suggest hypogonadotropic hypogonadism. A history of chemotherapy or radiotherapy may indicate primary gonadal failure. Physical exam should focus on previous height and weight measurements as well as Tanner stage. A testicular volume of >3 ml in boys indicates central puberty. Initial testing should include: serum chemistries, bone-age radiography, basal serum LH, FSH, IGF-1, thyrotropin, free thyroxine, and testosterone (in boys). LH and FSH are generally low in patients with CDGP or hypogonadotropic hypogonadism, whereas such levels are usually elevated in those with gonadal failure. Serum levels of insulin-like growth factor 1 (IGF-1) can be helpful in the evaluation of growth hormone deficiency but must be interpreted carefully because levels are often low for chronologic age but within the normal range for bone age. Brain magnetic resonance imaging (MRI) is indicated when there are signs or symptoms to suggest a lesion in the central nervous system.

Table 2. Investigations for Delayed Puberty.

Figure 1. Algorithm for the Evaluation of a Patient with Delayed Puberty.

Q: What are the options for treatment in a patient with CDGP?

A: The options for management of CDGP include expectant observation or therapy with low-dose testosterone (in boys) or estrogen (in girls). If puberty has started, clinically or biochemically, and stature is not a major concern, reassurance with realistic adult height prediction is frequently sufficient. The data suggest that treatment leads to increased growth velocity and sexual maturation and positively affects psychosocial well-being, without significant side effects, rapid advancement of bone age, or reduced adult height. Although the Food and Drug Administration has approved the use of growth hormone for the treatment of idiopathic short stature and height that is 2.25 SD below average for age, this therapy has at best a modest effect on adult height in adolescents with CDGP, and its use in CDGP is not recommended. In boys with CDGP and short stature, another potential therapeutic approach is aromatase inhibition, but this treatment requires further study before it should be incorporated into routine practice. Aromatase inhibitors block the conversion of androgens to estrogens; because estrogen is the predominant hormone needed for epiphyseal closure, the use of aromatase inhibitors could prolong linear growth and potentially increase adult height. However, potentially adverse effects, especially impaired development of trabecular bone and vertebral- ody deformities, which were observed in boys with idiopathic short stature who were treated with letrozole, must be considered.

Table 3. Medications for the Treatment of Constitutional Delay of Growth and Puberty (CDGP).

One Response to “Delayed Puberty”

  1. Benjamin says:

    Interesting article. However, I wonder whether time to puberty is actually normally distributed – in which case the mean and standard deviations are of little use. While physicians and scientists are used to thinking in terms of these standard measures of ‘spread’ (because most measurements are normally distributed), time-to-event data (another example being survival) is usually skewed and not symmetrically distributed. This is why the median and inter-quartile range are usually reported for such data. Is there evidence showing that time-to-puberty is normally distributed? If time-to-puberty is actually skewed in its distribution, using the 97.5th percentile as a cut-off may be more appropriate for determining CDGP.