Letrozole vs Anastrozole for Height Augmentation in Short Pubertal Males: First Year Data

Abstract

Context: Aromatase inhibitors are used off-label to treat short stature in peripubertal boys.Objective: To investigate short-and long-term hormonal and auxologic differences in short pubertal boys treated with letrozole (L) or anastrozole (A). Design:Patients are seen for laboratory evaluation and physical examination every 6 months, bone age yearly, DEXA and spine film every 2 years. They will be followed until they reach their final height. This is a preliminary report after 1 year of treatment.Setting: A single academic children's hospital outpatient clinic. Patients:Boys with age Ͼ10 years, bone age Յ14 years, clinical and hormonal evidence of central puberty, and either height Ͻ fifth percentile or predicted adult height (PAH) more than 10 cm below mid-parental height (MPH).Intervention: Letrozole (2.5 mg) or anastrozole (1 mg) was administered orally each day. Main Outcome Measures:Hormonal and clinical parameters, growth velocity, and change in bone age and PAH.Results: Thirty-nine boys have completed 1 year of treatment. Baseline means were age 14.1 years, PAH 166 cm, and testosterone 198 ng/dL. At 1 year, letrozole resulted in higher LH (L 6.1 Ϯ 2.5 vs A 3.2 Ϯ 1.7 IU/L) and testosterone (1038 Ϯ 348 vs 536 Ϯ 216 ng/dL) with lower estradiol (2.8 Ϯ 2.8 vs 5.6 Ϯ 2.9 pg/mL) and IGF-1 (237 Ϯ 51 vs 331 Ϯ 79 ng/mL). First year growth velocities were identical (7.2 cm/year), but an increase in PAH was greater in the anastrozole group (4.2 Ϯ 3.5 vs 1.4 Ϯ 4.4 cm, p ϭ 0.03) after 1 year. Conclusions:We present first-year data from a direct comparison of anastrozole and letrozole for height augmentation in short pubertal boys. Letrozole was more potent in hormonal manipulation than anastrozole. First-year growth velocities were comparable, but improvement in PAH was greater in the anastrozole group. It remains to be seen if positive PAH trends will translate to increase in final height in either group. A romatase is a cytochrome p450 enzyme that catalyzes the formation of C18 estrogens (estrone and estradiol) from C19 androgens (androstenedione and testosterone) (1). Two general types of pharmacologic aromatase inhibition have been developed to selectively inhibit estrogen synthesis: steroidal inhibitors compete with androstenedione for the substrate binding site, whereas nonsteroidal inhibitors bind to the heme group at the active site of the aromatase enzyme and block estrogen formation. Anastrozole and letrozole are the third generation

Anastrozole plus leuprorelin in early maturing girls with compromised growth: the “GAIL” study

“…It was also comparable to those of Mauras et al [ 7 ], in adolescent males with GHD and daily co-treatment with anastrozole, that resulted in a net increase in PAH of 6.8 cm at 36 months vs 1 cm in the placebo group. Similar results published recently by Neely EK et al showed a gain in PAH of 4.2 ± 3.5 cm in peripubertal boys with daily administration of anastrozole vs 1.4 ± 4.4 cm with letrozole after 1 year [ 5 ]. While AI have nowadays become an established—even if still an off-label treatment in boys—and this is proven by the fact that recent studies compare directly letrozole to anastrozole in short boys without even a control group [ 5 ], to our knowledge this is the first prospective study ever conducted in girls, outside the context of McCune Albright syndrome.…”

Letrozole Monotherapy in Pre- and Early-Pubertal Boys Does Not Increase Adult Height

“…Third generation aromatase inhibitors (AIs), such as letrozole (Lz) and anastrozole, are compounds that effectively suppress estrogen biosynthesis and have been shown to delay bone maturation in boys with growth hormone deficiency (GHD), constitutional delay of growth and puberty (CDGP), and idiopathic short stature (ISS) (1–4). The treatment with AIs has resulted in an increased predicted adult height (PAH) after 1–3 years of treatment (1, 3, 5, 6). These promising results have prompted the interest of using AIs for growth indications in adolescent boys (7, 8), albeit the long-term efficacy of the treatment on height gain lacks verification, since adult height data from controlled trials of AI-treated boys is limited to one study that included 6 boys with CDGP who received Lz for 1 year during mid-puberty (9).…”

Off‐label use of letrozole in Chinese short pubertal boys: Effectiveness, safety, and exposure–response analysis

“…Caucasian boys with the treatment of letrozole combined with testosterone (1.3-3.5 cm/year) or letrozole combined with growth hormone (3.9 ± 2.4 cm/year). 5,9,17,20,21,27 In all boys, E2 levels decreased, while T, LH and FSH levels increased. E2 levels have shown similar inhibited trend reductions in previous studies.…”

“…[13][14][15][16] It has been observed that the baseline E2 levels in Chinese boys are higher than in Caucasian boys. 7,9,[15][16][17][18][19][20][21] The pharmacokinetics of letrozole in adults shows substantial individual differences. 22,23 A recent study in boys with constitutional delay of growth and puberty suggests the required dosage may be lower than in adults and depend on weight.…”