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Editorial |
Department of Pediatrics/Endocrinology University of Utah Salt Lake City, Utah 84108
Address all correspondence and requests for reprints to: Dr. Carol M. Foster, Department of Pediatrics/Endocrinology, University of Utah, 615 Arapeen Drive, Suite 100, Salt Lake City, Utah 84108. E-mail: carol.m.foster{at}hsc.utah.edu.
Central precocious puberty is the premature activation of the hypothalamic-pituitary-gonadal axis. It is characterized by the increase in the amplitude and frequency of GnRH episodic release. The increase in GnRH, in turn, stimulates the synthesis and episodic release of gonadotropins, LH and FSH, stimulating gonadal steroid production and the premature development of secondary sexual characteristics. GnRH must be released episodically to produce an increase in gonadotropin secretion. On the other hand, continuous infusion of GnRH produces a profound suppression of gonadotropin secretion, with LH being suppressed more than FSH. GnRH agonist analogs, designed to have a long half-life, initially stimulate but then suppress gonadotropin synthesis and secretion. Central precocious puberty has been treated with GnRH agonist analogs for 25 yr. The first agonists had to be administered once or twice daily to maintain gonadotropin suppression. The subsequent development of sustained-release polymers permitted GnRH agonists to be administered at monthly or every-3-month intervals. Leuprolide acetate in its depot form is the most frequently used preparation for treatment of central precocious puberty in the United States. The recommended dose is 300 µg/kg every 28 d, and most pediatric endocrinologists begin treatment with 7.5 mg. Investigators in Europe have reported prevention of advancement of precocious puberty using a 3-month sustained release preparation containing 11.25 mg leuprolide acetate (1). Badaru et al. (2), in this issue, compared the degree of gonadotropin suppression induced by three different doses of depot leuprolide: the standard dose of 7.5 mg once a month, a second dose of 3.75 mg once a month, and third preparation of 11.25 mg in a different polymer given every 3 months. They found greater suppression of gonadotropin secretion using 7.5 mg depot leuprolide once a month than with either 3.75 mg monthly or 11.25 mg every 3 months. Thus, it appears that the current recommendation of 7.5 mg depot leuprolide monthly is preferable for treatment of children with precocious puberty. Several issues, however, must be considered before dismissing the convenience and utility of an every-3-month preparation of depot leuprolide.
It is exceedingly difficult to conduct good clinical trials in children. Clinical trials in children are subject to strict regulation and oversight, because children are considered a vulnerable population. Furthermore, because they are continuing to develop, children’s physical and hormonal profiles change with time. Badaru et al. (2) used a pragmatic study design optimized to decrease risk for the participating children. This resulted in a nonrandomized treatment order such that children first received 7.5 mg depot leuprolide monthly, then switched to 3.75 mg depot leuprolide monthly, and finally to 11.25 mg depot leuprolide every 3 months. Because children continued to grow and develop during the 1-yr study, an increase in gonadotropin secretion with time might have been expected, irrespective of the progressive decline in depot leuprolide dose. Because others have shown that 11.25 mg depot leuprolide every 3 months can adequately treat precocious puberty (1), it should be possible in the future to conduct a trial randomizing treatment without promoting excessive risks for this vulnerable population.
The second issue that must be considered is selection of the measurement used to determine treatment outcome. Badaru et al. (2) used gonadotropin suppression as the primary outcome measure. Most pediatric endocrinologists use gonadotropin concentrations to assess outcomes because they are reasonably sensitive and precise, unlike sex steroid measurements, physical signs of puberty, changes in height velocity, and changes in rate of bone maturation. If there were significant differences in the effect of drug dosage on the treatment of precocious puberty, sex steroid concentrations should also differ. Sex steroid concentrations, however, were similar during each of the three treatments. Ultimately the choice of depot leuprolide dosage should be based upon physical outcome rather than a laboratory result. Growth velocity was slowest in the group treated with 11.25 mg depot leuprolide every 3 months, indicating that these children were well suppressed, even though gonadotropin concentrations were highest in this group. The treatment goals for precocious puberty are halting the advancement of secondary sexual characteristics and decreasing the rate of bone epiphyseal maturation so as to achieve a normal final height. Consequently, treatment should not be governed simply by what produces "better" biochemical numbers.
Adverse events must always be considered in a drug trial. Of the 30 children enrolled by Badaru et al. (2), six failed to meet the stimulated gonadotropin threshold to be transitioned from 7.5 mg depot leuprolide to a lower dose, and four did not achieve the stimulated gonadotropin threshold during treatment with 3.75 mg depot leuprolide. The study duration, a total of 1 yr for all three depot leuprolide doses, was not sufficient to assess other side effects except for frequency of local reactions to injections. Potential long-term complications of GnRH agonist therapy for precocious puberty include decreased accretion of bone mass and development of obesity. Fortunately, the preponderance of long-term follow-up studies indicate that bone mass and body composition are not adversely affected by GnRH agonist therapy in children with precocious puberty. For children with short stature, however, delaying pubertal onset using a GnRH agonist resulted in significantly less bone mass at the study conclusion (3). The GnRH agonist used in this study was given daily and is more potent on a molar basis than is leuprolide acetate. The relationship between GnRH agonist dosage, degree of suppression of sex steroids and/or gonadotropins, and adverse events such as decreased bone mass accretion is unknown.
The children treated in the study by Badaru et al. (2) averaged 8.2 ± 1.4 yr of age. The age at appearance of secondary sexual characteristics was less than 8 yr in girls and less than 9 yr in boys. The children had either a spontaneous LH concentration of more than 0.3 IU/liter or a stimulated LH concentration greater than 6 IU/liter. The decision as to when to treat children with precocious puberty remains controversial. Differentiation between precocious thelarche and precocious puberty in girls remains difficult. Puberty has been considered abnormal if breast and pubic hair development begin before 8 yr of age or vaginal bleeding begins before 10 yr of age in girls and if secondary sexual characteristics appear before the age of 9 yr in boys. If rapid advancement of secondary sexual characteristics occur in a girl less than 7 yr of age or a boy less than 9 yr of age coupled with accelerated growth rate, bone age advancement 2 SD above the mean for chronological age, and increased gonadotropins, especially after pituitary stimulation with a GnRH agonist, most pediatric endocrinologists would agree that the benefits of treatment outweigh the risks. Recent studies of more than 17,000 children indicate that at least 15% of normal girls have breast development by age 8 yr, and early thelarche may not necessarily be associated with early onset of menses (4). Early appearance of secondary sexual characteristics associated with bone age advancement of more than 2 SD accompanied by rapid acceleration of growth velocity has also served as a means to define early pubertal development that warrants treatment. Obese girls, however, may be tall for their age, have advanced bone age, and have early breast development without apparent central activation of the hypothalamic-pituitary-gonadal axis. Few normative data regarding gonadotropin concentrations after GnRH stimulation are available to provide guidance. The GnRH agonist-stimulated LH concentration of greater than 6 IU/liter used in this study to indicate abnormal activation of the hypothalamic-pituitary-gonadal axis is based on measurements obtained from eight prepubertal girls and 13 prepubertal boys (5). We know that stimulated FSH concentrations decline progressively in childhood, reaching a nadir with the onset of secondary sexual characteristics (6), so that it is difficult to assess whether a 7-yr-old girl is truly in puberty or not. Although treatment with GnRH agonists should delay the onset of pubertal maturation, their use may not be necessary either to preserve height or to delay the onset of menses.
What should a physician do when confronted with a child whose pubertal development is earlier than that of his or her peers? Parents are alarmed that children will behave inappropriately, and there are controversial data indicating that girls with early puberty have more school problems and make more inappropriate choices in adolescence than do girls with average or late pubertal onset (7). Children less than 7 yr of age with rapid pubertal progression, bone age advancement, and pubertal gonadotropin concentrations should be treated with GnRH agonists and assessed at regular intervals. Girls who are 7 yr or older should be assessed carefully for pubertal tempo, and parents should be given advice as to the potential advantages and disadvantages of GnRH agonist therapy. Although it has been recommended that therapy be initiated as soon as possible to increase final height, observation for several months may be warranted to determine whether puberty is progressing rapidly or slowly. Slow progression of puberty in young girls is unlikely to be benefited by treatment. Boys with onset of puberty at less than 9 yr of age deserve careful evaluation for central nervous system disorders, as idiopathic precocious puberty is uncommon in boys. It is still unclear as to what dose of GnRH agonist is optimal at initiation of treatment. A dose of 11.25 mg of depot leuprolide given every 3 months is an appealing option because of its convenience, although this formulation is not currently approved by the United States Food and Drug Administration for precocious puberty. Hopefully this issue can be resolved by randomized studies conducted cooperatively among multiple centers.
Received March 1, 2006.
Accepted March 7, 2006.
References
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