Endocrine Abstracts

Constitutional delay of growth and puberty (CDGP) is the most common diagnosis among males and females with pubertal delay, but it can be diagnosed only after exclusion of other underlying conditions. Most of the boys with delayed puberty have CDGP, but about 5–10% have hypergonadotropic hypogonadism (including Klinefelter), 10% have permanent hypogonadotropic hypogonadism (including Kallmann syndrome and idiopathic hypogonadotropic hypogonadism), and 10% have a transient form of hypogonadotropic hypogonadism (delayed maturation of the HPG axis secondary to underlying conditions, e.g. inflammatory bowel disease).

Evaluation: First, exclude underlying disorders. Eventual normal progression of puberty verifies diagnosis of CDGP, whereas absent, slow or cessation of development is consistent with permanent hypogonadism. A complete family history is important, because CDGP clusters in families. Delayed puberty in a parent or sibling followed by spontaneous onset of puberty suggests CDGP. Bilateral cryptorchidism and/or small penis at birth, hyposmia, or anosmia suggest hypogonadotropic hypogonadism.

Previous height and weight measurements are also critical. Delayed puberty is often associated with short stature and slow growth for age, although height and growth velocity are usually appropriate for bone age. Individuals who are underweight for height have a higher likelihood of an underlying condition delaying HPG axis activation. Conversely, in boys, unlike girls, overweight is associated with later pubertal development. In boys, Tanner stage 2 genitalia and testicular volume of >3 cc indicates initiation of central puberty. Delayed bone age is not diagnostic of CDGP and is seen also in chronic illnesses, hypogonadotropic hypogonadism and gonadal failure. However, adult height prediction may be an important part of counselling if short stature is an issue.

Basal LH and FSH levels are low both in CDGP and hypogonadotropic hypogonadism. Conversely, in gonadal failure, basal levels are usually elevated. Patients with hypothalamic-pituitary tumours causing gonadotropin deficiency may have additional pituitary hormone deficiencies. After initial evaluation most patients with delayed puberty will have the likely diagnosis of CDGP. If basal gonadotropin levels are inconclusive, stimulation by GnRH may be helpful. Pubertal LH levels indicate reactivation of the HPG axis, and secondary sexual development is likely to occur within 1 year. However, the GnRH test alone often cannot differentiate CDGP from IHH because prepubertal values may be observed in IHH or in individuals with CDGP who have not yet activated the HPG axis. IHH can be diagnosed if endogenous puberty has not begun by age 18 years. Growth hormone secretion in the basal state, as well as after provocation testing, may be decreased in CDGP. If concerns about growth are sufficient enough to warrant growth hormone provocation testing, sex steroid priming is necessary for reliable results in patients with delayed puberty. A patient with a normal height velocity and a plasma IGF1 level above the mean for age does not require provocation testing.

In CDGP the options are observation or low dose testosterone or estrogen therapy in boys and girls, respectively. Therapy is usually initiated to assuage psychosocial concerns that may derive from difficulties with peers, decreased self-esteem, and anxiety about growth rate and/or body habitus. However, therapy is usually not initiated solely for medical reasons, such as accrual of bone mass.

Sex steroid 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. For a subset of patients with CDGP, short stature is as or more concerning than delayed puberty. Indeed, in various reports CDGP is considered a subgroup of idiopathic short stature and patient with CDGP do have low GH responses during provocation testing unless they are primed with sex steroids. GH treatment has a modest if any effect on adult height in adolescents with CDGP, and its routine use in CDGP is not recommended.

In patients with CDGP and short stature, an additional therapeutic approach is aromatase inhibition. Estrogen is the predominant hormone needed for epiphyseal closure, and therefore AIs could prolong linear growth and potentially increase adult height. However, characteristics of patients who respond and those who do not as well as the optimal timing, dose, and duration of AI treatment remain unresolved. The full side effect profile has also not been established. Thus, the use of aromatase inhibitors, even in adolescents with compromised predicted adult height, should be considered experimental.