Hospital Pharmacy Volume 38, Number 3, pp 222–226 2003 Wolters Kluwer Health, Inc.
Off-Label Drug Uses Letrozole: Delayed Puberty in Males Joyce Generali, RPh, MS, FASHP* and Dennis J. Cada, PharmD, FASHP, FASCP (Editor)†
Off-Label Drug Uses — This Hospital Pharmacy feature is extracted from OffLabel DrugFacts, a quarterly publication available from Facts and Comparisons. Off-Label DrugFacts is a practitioner-oriented resource for information about specific FDA-unapproved drug uses. This new guide to the literature will enable the health care professional/clinician to quickly identify published studies on offlabel uses and to determine if a specific use is rational in a patient care scenario. The most relevant data are provided in tabular form so that the reader can easily identify the scope of information available. A summary of the data— including, background, study design, patient population, dosage information, therapy duration, results, safety, and therapeutic considerations—precedes each table of published studies. References direct the reader to the full literature for more comprehensive information prior to patient care decisions. Direct questions or comments on “Off-Label Drug Uses” to hospitalpharmacy@drugfacts. com.
BACKGROUND Delayed puberty in males is usually diagnosed when pubertal events start late (usually more than 2.5 years [SD] later than the mean or no testicular enlargement by 14 years of age) or are attenuated in progression. Delayed puberty may have several causes, including constitutional delay of growth, chronic illness, or hypogonadotropism (eg, endogenous or chemically induced by radiation or chemotherapy). The exact role of androgens and estrogens in the regulation of pubertal growth is not fully understood. It was suggested recently that estrogens are necessary for epiphyseal closure. In addition, in boys, estrogens may regulate LH secretion negatively in the early
*Director, Drug Information Center, Kansas University Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160;
[email protected]; †Editor-in-Chief, Hospital Pharmacy and Executive Editor, The Formulary.
222
Volume 38, March 2003
and mid-pubertal stages. In contrast, androgens may regulate LH secretion negatively in late puberty. (Wickmann 2001). Thus, suppression of estrogen in early or delayed puberty may delay bone maturation and increase the potential for full height realization. STUDY DESIGN 1 Randomized, double-blind, placebocontrolled, parallel trial: 33 patients PATIENT POPULATION The study enrolled adolescent males with a diagnosis of delayed puberty, short stature, or both. DOSAGE AND DURATION Letrozole 2.5 mg once daily for 1 year was coadministered with six doses of testosterone enanthate (IM) given every 4 weeks. RESULTS Letrozole for delayed puberty was studied in only one small, double-blind-
ed trial, which was published in three journals (Wickman et al 2001; Dunkel and Wickman 2001; Wickman and Dunkel 2001) The most comprehensive publication has been selected for review (Wickman et al 2001). In this trial, 33 adolescent males with a diagnosis of delayed puberty, short stature, or both were recruited. A total of 23 boys were randomized to receive testosterone injections with letrozole or with placebo. Ten boys decided to forego medical treatment and wait for spontaneous progression of puberty. This untreated group was used as a control group. At baseline, there were no differences between the groups in chronological age, height, bone age, predicted adult height, pubertal stage, testis volume, bone mineral density, or mean concentrations of hormones (eg, 17Bestradiol, LH, FSH, testosterone). Estradiol concentrations were significantly increased in the untreated group by 90% at 12 months and in the testosterone plus placebo (“placebo”) group by 130% at 5 months. In contrast, there were no significant changes in 17B-estradiol levels in the testosterone plus letrozole (“letozole”) group for 12 months. However, estradiol levels were comparable among all groups at 18 months (6 months after treatment was stopped). Testosterone concentrations remained the same in the untreated group over the 12-month study period. However, at 2-month assessment, testosterone concentrations had increased by 33% in the placebo group (11.9 vs 15.8 nmol/L) and by 420% in the letrozole group (9.5 vs 49.1 nmol/L).
Citation
Indication
Study Design
Patient Population/Profile
Drug (Route) Dose (Duration)
Results
Wickman et al. 2001
Delayed male puberty
Randomized; doubleblinded; placebocontrolled
33 boys with diagnosis of either constitutional delay of puberty (defined as Tanner genital or pubic hair stage observed at an older age than the mean + 2 SD for healthy Finnish boys) or a testis volume < 4 mL after 13.5 years
Group 1: Letrozole (PO): 2.5 mg once daily x 1 year with Testosterone enanthate (IM): 1 mg/kg every 4 weeks x 6 doses
Clinical Outcomes
Groups I & II: Mean age: 15.1 years (range: 13.5 to 16.1 years) Group III: Mean age: 15 years (range: 14.4 to 16.8 years)
Group II: Placebo (PO): Once daily x 1 year with Testosterone enanthate (IM): 1 mg/kg every 4 weeks x 6 doses Group III: Control Group (untreated)
Safety
Hormonal Changes 17B-estradiol concentration at 12 months Untreated +90% PLB/TST +130% (5 months) LET/TST 0% After letrozole treatment was stopped, 17B-estradiol levels increased and were similar to placebo group’s by 18 months. LH Concentrations (IU/L) 8 Wks BSL PLB/TST1 1.9 0.3 2.5 7.8 LET/TST2 At 12 months, LH levels returned to baseline in PLB/ TST group and remained elevated in LET/TST group. After treatment was stopped, LH levels were similar in all three groups.
Hospital Pharmacy
Testosterone Concentrations (nmol/L) 8 wks BSL PLB/TST3 11.9 15.8 9.5 49.1 LET/TST4 High levels maintained in Letrozole group until treatment stopped, after which concentrations decreased to levels comparable with other groups. (continued)
Author Conclusions
Off-Label Drug Uses
Letrozole: Delayed Puberty in Adolescent Males
223
Volume 38, March 2003
Citation
Indication
Study Design
Patient Population/Profile
Wickman et al. 2002 (cont.)
Drug (Route) Dose (Duration)
Results
Growth Velocity (cm/year) UT 0–5 months5 7.3 5–12 months 6.6 12–18 months 6.5
P/T 9.9 7.9 6.5
Bone Age Increases in 1.5 years Untreated 1.1 years PLB/TST6 1.7 years LET/TST6 0.9 years Predicted Adult Height (PAH) PAH did not change significantly in the untreated or PLB/TST groups after 1.5 yrs. In contrast, PAH had an increase of 5.1 cm in the LET/TST group (P = 0.004). The difference in change in height between the treatment groups was significant (P = 0.04).
Abbreviations BMD = Bone mineral density BSL = Baseline LET = Letrozole LH = Luteinizing hormone L/T = Letrozole/testosterone PAH = Predicted adult height PLB = Placebo P/T = Placebo/testosterone TST = Testosterone UT = Untreated
Secondary Sexual Changes Gynecomastia found in none of the untreated group and in two patients in each of the treatment groups. Testis volume was significantly greater in the LET group vs. the PLB group at 5 months and 12 months. Bone Mineral Density (BMD) BMD of the lumbar vertebrae increased in both treatment groups at 12 and 18 months. BMD in femoral neck significantly increased only in the PLB group. 1
P = 0.003; BSL vs 8 weels P = 0.004; BSL vs. 8 weeks 3 P = 0.02; BSL vs 8 weeks 4 P = 0.001; BSL vs 8 weeks 5 P = 0.02 6 P = 0.02; PLB vs LET 2
L/T 7.3 7.1 8.3
Safety
Author Conclusions
ADR Profile No ADRs reported
Results suggest that inhibiting estogen action in adolescents may increase adult height potential in patients with delayed puberty.
Off-Label Drug Information
224 Letrozole: Delayed Puberty in Adolescent Males (Continued)
Off-Label Drug Information
The high concentrations in the letrozole group were maintained over the 12month period, until treatment was stopped. At this time, testosterone levels were comparable among all three groups. In the treatment groups, boys in the placebo group grew slightly faster than the letrozole group during the first 5 months. After 5 months, the growth velocity was similar between the two groups. Over an 18-month period, letrozole delayed bone maturation, which advanced 0.9 years, 1.1 years, 1.7 years in the letrozole, untreated and placebo groups, respectively. The authors suggested that inhibition of estrogen synthesis by letrozole was responsible for delayed bone maturation in this group. They suggested that these results indicate that estrogen may be more influential than androgens in bone maturation in pubertal boys. Predicted adult height was significantly increased in the letrozole group by 5.1 cm. Study Limitations Published comments about this study suggest that the results are limited by its small enrollment, which did not allow assessment of significant differences in spinal growth among groups (Stanhope 2001. The study has also
226
Volume 38, March 2003
been criticized for enrolling boys younger than 14 years (the age used to define delayed puberty) and enrolling some boys already in early or midpuberty. Other criticisms were that the adult height projections were in excess of the fiftieth percentile in the US (Malozowski 2001). However, the authors stated that they had used the guidelines for the Finnish population, which define delayed puberty at 13.5 years (Dunkel 2001). SAFETY Gynecomastia, a sign of estrogen excess, was found in none of the boys in the untreated group and in 2 boys in each of the treatment groups. No adverse events attributed to drug therapy were reported in the trial. THERAPEUTIC CONSIDERATIONS The use of letrozole in delayed puberty has been studied by one set of investigators and published in three different journals. Although the growth benefits associated with estrogen inhibition in this study may be valid, these results need to be confirmed in larger, long-term, controlled trials before routine use can be recommended in boys with delayed puberty.
REFERENCES Dunkel L, Wickman S. Treatment of delayed male puberty: Efficacy of aromatase inhibition. J Pediatric Endocrinology & Metabolism. 2001;14: 1541–6. Wickman S, et al. A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: A randomised controlled trial. Lancet. 2001;357:1743–8. Wickman S, Dunkel L. Inhibition of P450 aromatase enhances gonadotropin secretion in early and midpubertal boys: Evidence for a pituitary site of action of endogenous E. J Clin Endocrinol Metab. 2001;86:4887–94.
SUGGESTED READINGS Dunkel L. Role of hormones in puberty. Lancet. 2001;358:1459–60. Malozowski S. Role of hormones in puberty. Lancet. 2001;358:1459. Reiter EO, Lee PA. Delayed puberty. Adolesc Med. 2002 Feb;13(1):101–8. Rosen DS, Foster C. Delayed puberty. Pediatr Review. 2001;22(9):309–15. Stanhope R. Use of a specific aromatase inhibitor in delayed puberty [editorial]. Lancet. 2001;357:1723–4. Traggiai C, Stanhope R. Delayed puberty. Best Pract Res Clin Endocrinol Metab. 2002;16(1):139–51. !
