The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study.
The management of the growth-retarded child who is in the midst of puberty is an area of common difficulty in pediatric endocrinology practice. Regardless of the etiology of the growth retardation, attempts to increase height potential during puberty often are complicated by the inexorable tempo of epiphyseal fusion caused by the pubertal sex steroids, greatly limiting the time available for linear growth. Several strategies have evolved that attempt to increase height potential in growth hormone (GH)- deficient children who are in puberty, or in those who have idiopathic short stature, some of which are summarized in this article.
High-dose growth hormone
During human puberty, there is an approximate doubling of GH production rates, with peak production coinciding with peak height velocity. This increase in GH secretory rates is mediated, at least in part, through sex steroid hormones, and in both testosterone-treated and estradiol-treated prepubertal children, there is an augmentation of the GH production rates, mostly as an amplitude-modulated phenomenon, relatively independent of changes in pulse frequency. The author and colleagues performed a randomized study designed to compare the efficacy and safety of standard recombinant human GH therapy (0.3 mg/kg/wk) versus high-dose therapy (0.7 mg/kg/wk) in GH-deficient adolescents previously treated with GH for at least 6 months. Ninety-seven GH-deficient children participated (83 boys, 14 girls), of whom 48 completed the study. The author and colleagues observed that a mean of 3 years of high-dose GH therapy to GH-deficient adolescents was associated with a statistically significant increase in near-adult height of 4.6 cm over that observed in children treated with standard doses of GH. In those treated for 4 years, the increase was 5.7 cm. This was not associated with an undue advancement of skeletal maturation, alteration of the tempo of puberty, or greater frequency of adverse events. The mean height SD score at near-adult height was −0.7 plus or minus 0.9 in the standard dose group and 0.0 plus or minus 1.2 in the high-dose group ( Fig. 1 ). Median plasma insulin-like growth factor (IGF)-I concentrations at baseline were 427 μg/L (range, 204 to 649) in the standard-dose group and 435 μg/L (range, 104 to 837) in the high-dose group. At 36 months, they were 651 μg/L (range, 139 to 1079) versus 910 μg/L (range, 251 to 1843) in the standard- and high-dose groups, respectively ( P = not significant [NS]). There were no differences in any measures of carbohydrate metabolism. No difference in change in bone age was detected between groups at any interval.
The author and colleagues concluded from these data that high-dose GH therapy, administered during a finite window of time, may be beneficial and safe for increasing the final adult height of youngsters with GH-deficiency who are in the midst of puberty. Although these data led to the US Food and Drug Administration (FDA) approval of high-dose GH in puberty, the results were not meant to imply the need for an automatic increase in the dose of GH when the child reaches puberty (ie, if a child is growing well, there should be no need to increase the dose of GH). High-dose GH may be particularly useful, however, in selected cases of those most growth-retarded at the start of puberty. This strategy warrants careful monitoring of IGF-I and glucose concentrations and continued surveillance for adverse events.
GnRH analog
Because the principal culprit for epiphyseal fusion is the presence of pubertal sex steroids, the use of GnRH analogs has been tried in an effort to slow down fusion of the growth plate. Abundant data show that suppressing the production of sex steroidal hormones delays epiphyseal fusion and ultimately can render youngsters with precocious puberty taller than they would be otherwise. The use of GnRH analogs in precocious puberty subjects accomplishes a biochemical castration and ultimately renders patients taller by delaying the timing of bone fusion. This strategy has been tried not only in children with sexual precocity but in those with GH-deficiency who are in physiologic puberty and even in those with short stature not caused by GH-deficiency who are also in puberty, with mixed results. In the patients treated with both GH and GnRH analog, improvements in height predictions (as determined by bone ages) have ranged from 7.9 cm to 14 cm when the children were treated for 2 to 4 years. This therapy has been less successful in augmenting final height when used alone in children with normal variant short stature and normally timed puberty, and a recent consensus conference on the use of GnRH analogs could not recommend the routine use of GnRH analogs in such setting.
The consequences of this approach, as it pertains to bone accretion/bone density, and the psychological impact of suppressing the timely course of puberty in an already short child, have not been studied appropriately, however. Even 10 W of GnRH analog therapy in healthy young adult males is associated with substantial changes in body composition and intermediate metabolism, with increased adiposity, decreased rates of protein synthesis, decreased lipid oxidation, decreased energy expenditure, and decreased muscle strength. Using stable tracers of calcium, the author’s group’s studies in GnRH analog-treated males show a marked increase in urinary calcium losses and bone calcium resorption rates, indicating the crucial role of sex steroidal hormones in bone mineralization, even in the male. Hence in physiologically timed, normal puberty, GnRH analogs should not be used as monotherapy.
GnRH analog
Because the principal culprit for epiphyseal fusion is the presence of pubertal sex steroids, the use of GnRH analogs has been tried in an effort to slow down fusion of the growth plate. Abundant data show that suppressing the production of sex steroidal hormones delays epiphyseal fusion and ultimately can render youngsters with precocious puberty taller than they would be otherwise. The use of GnRH analogs in precocious puberty subjects accomplishes a biochemical castration and ultimately renders patients taller by delaying the timing of bone fusion. This strategy has been tried not only in children with sexual precocity but in those with GH-deficiency who are in physiologic puberty and even in those with short stature not caused by GH-deficiency who are also in puberty, with mixed results. In the patients treated with both GH and GnRH analog, improvements in height predictions (as determined by bone ages) have ranged from 7.9 cm to 14 cm when the children were treated for 2 to 4 years. This therapy has been less successful in augmenting final height when used alone in children with normal variant short stature and normally timed puberty, and a recent consensus conference on the use of GnRH analogs could not recommend the routine use of GnRH analogs in such setting.
The consequences of this approach, as it pertains to bone accretion/bone density, and the psychological impact of suppressing the timely course of puberty in an already short child, have not been studied appropriately, however. Even 10 W of GnRH analog therapy in healthy young adult males is associated with substantial changes in body composition and intermediate metabolism, with increased adiposity, decreased rates of protein synthesis, decreased lipid oxidation, decreased energy expenditure, and decreased muscle strength. Using stable tracers of calcium, the author’s group’s studies in GnRH analog-treated males show a marked increase in urinary calcium losses and bone calcium resorption rates, indicating the crucial role of sex steroidal hormones in bone mineralization, even in the male. Hence in physiologically timed, normal puberty, GnRH analogs should not be used as monotherapy.
Aromatase inhibitors
A large body of experimental and human data has shown that estrogen, in both females and males, is a principal regulator of epiphyseal fusion. This is evidenced by detailed studies of male patients with point mutations either in the estrogen receptor gene or in the aromatase enzyme gene, who grew to significantly tall heights because of the lack of estrogen effect. When an estrogen receptor blocker was given to estrogen-treated mice, the acceleration in bone maturation caused by estrogen was blocked, supporting further the effect of estrogen on bone maturation. Animal data suggest that the estrogen receptor β (ERβ) is the principal physiologic inhibitor of axial and appendicular growth. The availability of aromatase inhibitors now allows the possibility of studying their use in growth disorders in greater detail.
Pharmacology
Aromatase inhibitors are a class of compounds that block aromatase, a microsomal P450 enzyme product of the CYP19 gene, which catalyzes the rate-limiting step in the production of estrogens (ie, the conversion of testosterone to estradiol and androstenedione to estrone). Enzyme activity is present in many tissues, including the ovary, breast, brain, muscle, liver, and adipose tissues among others. Over the last decades, several aromatase inhibitors have been developed with relatively weak suppression of the enzyme and hence variable clinical response. These compounds (eg, testolactone, fedrozole) also had some significant adverse effects. A third generation of aromatase inhibitors has been developed with much more potent blockade of the aromatase enzyme and greater safety profiles. There are three of these drugs on the market in the United States for treating breast cancer in postmenopausal women, including anastrozole, letrozole, and exemestane ( Fig. 2 ). The author and colleagues have conducted studies on the pharmacokinetic properties of exemestane, and more recently anastrozole in young males, and they have found similar properties as those in post menopausal women. These aromatase inhibitors are absorbed after oral administration and are given once daily, with a terminal half-life of approximately 45hrs (30–60) and either hepatic or renal clearance. Anastrozole (compounded as 1 mg tablets) and letrozole (2.5 mg tablets) are reversible inhibitors of the enzyme and are nonsteroidal, whereas aromasin (25 mg tablets) is a steroid analog of androstenedione and an irreversible inhibitor of aromatase. Neither anastrozole nor letrozole absorption are affected significantly by food, so they can be taken at any time. Exemestane’s absorption, however, is enhanced by food intake, particularly fatty foods, so it is best to have patients take the drug with a meal.
Physiologic Studies
To better characterize the metabolic effects of estrogen suppression in males, the author and colleagues administered 10 weeks of 1 mg of anastrozole to young healthy men ages 18 to 25 years. The author observed no negative effects of estrogen suppression on a host of metabolic measures, including lipid concentrations, liver profiles, complete blood cell counts (CBCs), bone formation markers, and body composition measures, as well as measures of whole-body protein synthesis and calcium turnover. This was despite a 50% reduction in circulating estradiol concentrations measured by a recombinant cell bioassay. This is in sharp contrast to the deleterious effects of GnRH analog therapy described by the author’s group in males, suggesting that at least during a finite window of intervention, aromatase inhibitors did not have catabolic effects like GnRH analogs ( Fig. 3 ).
Studies in Boys with Disorders of Growth
A group of boys in Finland who had history of constitutional growth delay were treated for 5 months with intramuscular testosterone and either letrozole (2.5 mg) or placebo tablets daily for 12 months. Six months after discontinuation of the tablets, bone ages were examined to predict adult height, and there was a statistically significant increase in predicted adult height above that of those treated with placebo of +5.9 cm ( P = .04). These boys have been followed to final adult height, and the projected height increase was found to hold after treatment discontinuation. There were significant increases in circulating testosterone concentrations due to the rise in gonadotropins caused by the aromatase blockade, some of which were supraphysiological.
The same group of investigators extended their use of letrozole given as monotherapy for 2 years to a group of boys who had idiopathic short stature. They recruited 31 boys, 27 of whom were prepubertal at study entry, and treated with either letrozole (2.5 mg) or placebo. The investigators observed a significant slowing of bone age acceleration, an increase in height predictions, and taller height standard deviation score (SDS) for bone age in the letrozole group compared with the placebo group. Testosterone concentrations increased significantly more in the letrozole group; however, the investigators reported no advancement in the timing of puberty onset. The drug was tolerated well, but IGF-I concentrations were lower in the letrozole group. The latter is an important marker to follow, especially in those subjects using this class of drugs as monotherapy. Bone mineral density accrual was reported to be comparable in both groups.
Recently, we reported the results of a double-blind, randomized, placebo-controlled clinical trial in the United States to investigate whether treatment with a selective and potent aromatase inhibitor (anastrozole) could delay the rate of bone age maturation and whether it increases adult height potential in GH deficient adolescent boys also treated with GH. The use of anastrozole resulted in a significant delay in the tempo of bone age acceleration as compared with placebo in adolescent boys with GH deficiency who also were treated with GH. This slowing of epiphyseal fusion caused by estrogen blockade resulted in a significant net gain in predicted adult height from baseline, as calculated based on bone age, of +4.5 (1.2) cm and +6.7 (1.4) cm after 2 and 3 years respectively, as compared with +1 cm at both time points in the placebo group. This translated into a net gain from baseline in height SDS adjusted for bone age in the anastrozole versus the placebo group ( Fig. 4 ). The author and colleagues intentionally targeted an age range in which a natural deceleration of growth occurs after peak growth velocity. The decrease in growth velocity during the course of these studies was also greater in the placebo group than in the anastrozole group at 36 months. Bone mineral density accrual by dual energy x-ray absorptiometry (DEXA) was comparable in a subset of patients who had DEXAs performed. In a prospective, double-blind, randomized, placebo-controlled clinical trial, investigators in Iran studied 91 boys (12.6–14.6 years old) with constitutional growth delay and predicted adult short stature treated with either letrozole (2.5 mg/day), oxandrolone (2.5 mg/day), or placebo for 2 years. They reported that letrozole differed from oxandrolone and placebo in significantly increasing predicted adult height, and slightly but significantly decreasing HDL-cholesterol. However, both oxandrolone, and to a lesser degree letrozole, significantly increased the height standard deviation score and bone age compared to placebo. Letrozole had a good safety profile over 2 years. In aggregate, data thus far suggest that aromatase inhibitors are effective in slowing down bone age progression and increasing adult height potential. These cohorts need to be followed to adult height. Ongoing trials will hopefully provide more information regarding efficacy in adult height promotion in this patient population.
