Current clinical management of constitutional delay of growth and puberty

To make a correct diagnosis the clinician should follow a simple iter [7]. After a detailed medical history and a correct auxological evaluation including height, weight, growth rate and evaluation of pubertal development and its progression, a clinical examination aimed at identifying particular signs should be done. CDGP occurs in healthy adolescents with an height reduced considering chronological age but appropriate considering bone age and pubertal development, which are delayed as well. In particular, CDGP adolescents may show a peripubertal deceleration of growth velocity (slowing down) associated with both delayed pubertal development and bone maturation [8]. The diagnosis requires the exclusion other causes of pubertal delay mainly organic, genetic and nutritional diseases, such as intestinal malabsorption, subclinical hypothyroidism or cystic fibrosis. A close relation between the stages of pubertal development and the start of pubertal spurt has been suggested. The pubertal growth spurt is usually observed in girls at the first stages of breast, approximately at Tanner II and III stage, while in boys when testicular volume reaches 10-12 ml. Loss of the normal harmony of growth and puberty could suggest an endocrinopathy. However, the normal consonance of growth and pubertal development is characteristic of the subjects with CDGP who do not require specific investigation. Distinguishing between CDGP and HH is especially difficult during initial evaluation because adolescents with these aetiologies are often prepubertal. Neither baseline nor GnRH stimulated gonadotropin levels are capable to differentiate CDGP from permanent hypogonadotropic hypogonadism [7]. Recently, new developments raise the availability of differentiate CDGP from CHH in the clinical setting [9]. The FSH-stimulated inhibin B has been shown to correctly differentiate pubertal delay from a hypogonadoptrophic hypogonadism; however further studies are need to confirm this interesting point [10]. A family history of DP strongly suggests a condition of CDGP (observed in 50–75%). The main characteristics of the three groups are summarized in Table 1. (Table 1) Generally, delayed puberty is a transient condition and has a good prognosis both in terms of final height and of reproductive ability. As growth potential is related to the degree of epiphyseal maturation, bone age delay allows a final stature within the normal range. Actually, there is no consensus whether boys with DP may reach a final height related to the target height [11]. Either the precise and timely diagnosis of CDGP and the elimination of possible pathological growth patterns are useful to an adequate management of CDGP. The classification of pubertal delay is based on a precise anamnestic investigation and a careful examination with the exclusion of either dysmorphic syndromes and systemic diseases. In some cases a physical examination alone may be sufficient.

The indication of treating CDGP is limited to prepubertal subjects who are older than 14 years of age and have serious psychological distress, mainly correlating to bullying. In girls with CDGP, treatment with a limited dose of estradiol (5-10 mcg daily) for up to 12 months is rare and should led to breast development. Hormonal treatments should be carefully prescribed not to stimulate acceleration in skeletal maturation and not to increase the consequent risk of reduced stature. In fact, in cases of constitutional DP, the best course of action is patience and reassurance. In males a cycle of 50 mg/month of testosterone, increased to 100 mg after 6 months may be offered if psychological problems are exacerbated by the delay [12]. Another possibility is transdermal testosterone administration, beginning with one puff every second day for 3 months, increasing the dosage progressively [13]. During treatment a progressive increase of the testicular volume confirms the diagnosis of CDGP. The treatment should continue until a volume of 12 ml is reached, since at that point the boy can produce a substantial amount of testosterone allowing a normal growth. Therefore, the start of treatment should be individualized depending mainly on the psychological repercussions including low self-esteem, poor school performance, depression and bullying [12]. On the other hand, in hypo- or hyper-gonadotropic hypogonadism long-term hormone substitutive therapy is advised. Girls usually start on a low dose of estrogen administered orally with tablets (5-10 μg/Kg per day) or through transdermal patches every 3-4 days per week, for cycles of 6 months until breast development reaches Tanner III stage. Because of individual variability in the absorption of estradiol, serum estradiol values must be monitored. In 1 year, progesterone is added to facilitate the menstrual cycle and to increase bone density in puberty. Boys usually start with intramuscular injections of 50 mg/month of testosterone for 6 months, rising progressively the dose until an adult dosage (250 mg/month) is reached. However, as for stature, data are not consistent with the indication of growth hormone therapy in increasing adult height in subjects with reduced height and delayed puberty, particularly in the female sex [14]. While, in cases of significant pubertal delay, if no sex steroid hormones treatment is started, acquisition of bone mass can be reduced leading in adulthood to a major risk of future fractures mainly in men [15]. Current studies do not demonstrate that initial testosterone therapy impairs future fertility in boys with PHH; however, if new studies were to demonstrate superiority of early gonadotropin treatment, identifying youth with CHH may guide therapy. Thus, the identification of a generalizable, economic and easily administered diagnostic test for delayed puberty still remains an important endpoint for researchers [9]..