Gonadotropin-Releasing Hormone Analog Therapy for Central Precocious Puberty and Other Childhood Disorders Affecting Growth and Puberty

Gonadotropin-releasing hormone (GnRH) analog therapy relies primarily on the ability of these compounds to bind to and modulate GnRH-receptor activity. GnRH analogs have been used in pediatric patients where endogenous gonadotropin release is undesirable or potentially harmful, such as in: (i) patients with central precocious puberty (CPP); (ii) healthy short children where pubertal delay would provide an opportunity to supplement pre-pubertal linear growth; and (iii) children with malignancies and other disorders where treatment requires the use of gonadotoxic compounds. In the first two groups of patients, GnRH agonists may be used alone or in conjunction with somatropin (growth hormone [GH]) to prevent early skeletal maturation and increase the subsequent adult height, while in the latter case, GnRH agonists are used alone or in conjunction with GnRH antagonists in an attempt to preserve gonadal function. In children and adolescents with CPP, timely use of GnRH agonists alone can result in an adult height within the genetic potential of the individual (target height); however, minimal height is gained when GnRH agonist therapy is commenced after a marked advancement of skeletal age. This provides the rationale for combined therapy with GnRH agonists and somatropin in such patients, and studies have shown improved growth with this approach compared with GnRH agonists alone. Combination therapy with GnRH agonists and somatropin has also been shown to increase adult heights to a greater extent than GnRH agonists alone in pediatric patients with concomitant CPP and GH deficiency, those with idiopathic short stature, and those born small for gestational age; however, such combination therapy has shown no increased benefit over somatropin alone in pediatric patients with GH deficiency. Limited results in children and adolescents with congenital adrenal hyperplasia and chronic primary hypothyroidism have also shown increased growth rates, while no growth benefit was seen in pediatric renal transplant recipients. GnRH analogs also have potential as gonadoprotective agents; studies of GnRH agonists used alone and in combination with GnRH antagonists in women undergoing cytotoxic therapy have shown increased preservation of reproductive potential in patients who were receiving GnRH analog therapy versus those who were not. The adverse effects of GnRH analogs mainly consist of menopausal-like complaints. Increases in body weight and body mass index in children receiving GnRH agonist therapy have been shown; however, these increases do not persist after discontinuation of therapy. Adult bone mineral density and fertility are also not adversely affected by childhood GnRH agonist therapy. GnRH analog therapy appears to be both well tolerated and effective in pediatric patients, as it allows the preservation or improvement of adult height, and shows no longstanding negative effects on body composition, bone density, reproductive function, or endocrine physiology. These agents may also be useful for preservation of gonadal function in children and adolescents undergoing cytotoxic therapy.