ABSTRACT
Conclusion:
No meta-analysis is available which has analysed the role of letrozole in constitutional delay in growth and puberty (CDGP). Electronic databases were searched for randomized controlled trials (RCTs) involving children with CDGP receiving letrozole. Primary outcomes were changes in predicted adult height (PAH) and pubertal progression. Secondary outcomes were alterations in bone age (BA), hormonal markers of puberty, bone mineral density and side-effects. One hundred-thirty articles were reviewed, from which seven RCTs which fulfilled all criteria were analysed. Letrozole was superior to placebo [mean difference (MD) 4.63 cm (95% confidence interval (CI): 3.90-5.36); p<0.01; I2=0%] but not testosterone [MD: 2.21 cm (95% CI: -1.71-6.16); p=0.27; I2=98%] with regards to improvement in PAH after 12-months use. Letrozole was superior to both placebo [MD: 4.80 mL (95% CI: 0.57-9.03); p=0.03] and testosterone [MD: 3.36 mL (95% CI: 0.58-6.75); p=0.02; I2=0%] with regards to improvement in testicular volume after 12-months use. Letrozole tended to be superior to testosterone [MD: -0.84 years (95% CI: 2.83-8.18); p=0.06; I2=0%] with regards to slowing in BA progression after 12-months use. Serum luteinizing hormone, follicle stimulating hormone, testosterone and inhibin-B were significantly higher after 6-months letrozole use compared to active as well as passive controls. No increased occurrence of adverse events, including spinal deformities, were noted with letrozole. Letrozole is safe and effective for improving height and pubertal outcomes in CDGP, and is better than testosterone with regards to improvement in testicular volume and may be better at delaying bone-age progression.
Introduction
Constitutional delay in growth and puberty (CDGP) is perhaps the most common cause of short stature in both the sexes; and for not yet determined reasons, is much more common in boys than girls (1). The diagnosis of CDGP is often a diagnosis of exclusion (2). Children with CDGP have delayed pubertal growth spurt and usually have catch-up growth with the late onset of puberty, by 18 years age (2). Although reassurance and watchful waiting is recommended in CDGP, many children with CDGP in their teenage years have associated significant psychosocial stress, negative interaction with peers, anxiety or depression, warranting medical intervention (3). Suggested interventions include medications which will promote sexual maturation (4). Traditionally, low dose testosterone injections/oxandrolone and ethinyl estradiol/estradiol patches have been tried to accelerate puberty in boys and girls, respectively, for many decades now (4). Recently a few trials have been published which have suggested that letrozole may have a role in activation of the hypothalamic-pituitary-gonad (HPG) axis and faster testicular growth, resulting in accelerated height growth and pubertal progression in CDGP (5,6).
Theoretically, aromatase inhibitors are uniquely suited to manage different aspects of CDGP. Letrozole would delay bone maturation by inhibiting conversion of testosterone to estradiol and thereby lowering blood estradiol concentrations (7). Letrozole also has the potential to induce maturation of the HPG axis by decreasing the negative feedback loop from estradiol to the hypothalamus. Some safety concerns include reduced bone density, which have primarily been documented in adult cancer survivors (8).
However, to date, no meta-analysis is available which has holistically analysed and summarized the clinical efficacy and safety of letrozole in CDGP. Hence the aim of this meta-analysis was to evaluate the efficacy and safety of letrozole in the management of CDGP.
Methodology
The meta-analysis was carried out according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (9). The predefined protocol has been registered in PROSPERO, having the registration number CRD42021250345. All randomized controlled trials (RCTs) published up to March 2021 were considered for this meta-analysis. This meta-analysis has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, the filled checklist of which can be found at the end of the manuscript (9). Since ethical approval already exists for the individual studies included in the meta-analysis, no separate approval was required for this study.
The PICOS criteria was used to screen and select the studies for this meta-analysis with patients (P) being children diagnosed with CDGP; intervention (I) being the use of letrozole for managing CDGP; control (C) being patients either on placebo or any other approved medication for managing CDGP, which included testosterone, oxandrolone or estradiol; outcomes (O) being evaluated were impact on predicted adult height (PAH), height standard deviation score (Ht-SDS), bone age (BA), clinical and hormonal measures of puberty and any adverse effects noted; and (S) being studies included which were RCTs. Only children with CDGP were considered for this meta-analysis. Children with other forms or causes of short stature, such as familial short stature, growth hormone deficiency, panhypopituitarism, syndromic short stature, and idiopathic short stature were excluded. Only those studies were included in this meta-analysis which had at least two treatment groups of children with CDGP, with one of the groups receiving letrozole and the other group receiving either placebo or any other medication in place of letrozole.
The primary outcomes were to evaluate the changes in PAH and pubertal progression, as determined by testicular volume. The secondary outcomes were to evaluate the alterations in Ht-SDS, final height, BA, hormonal markers of puberty [including testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, inhibin-B, and anti-Müllerian hormone], bone mineral density (BMD), body composition changes (lean mass, fat mass), and any side effects reported. Analysis of the growth and puberty outcomes was based on whether the control group received an active comparator (like testosterone, oxandrolone or any other approved medication for use in CDGP) - labelled here as the active control group (ACG) or a placebo/nothing - labelled as passive/placebo control group (PCG).
Search Method for Identification of Studies
A detailed search was done of electronic databases of Medline (Via PubMed), Embase (via Ovid SP), Cochrane central register of controlled trials (CENTRAL) (for trials only), ctri.nic.in, clinicaltrials.gov, global health and Google scholar using a Boolean search strategy: (letrozole) AND [(delayed puberty) OR (short stature)].
Data Extraction and Study Selection
Data extraction was carried out independently by two authors using standard data extraction forms. In cases where more than one publication of a single study group were found, results were grouped and relevant data from each report were used in the analyses. Data on the primary and secondary outcomes, as stated above, was extracted. Patient characteristics (including demographic information and comorbidities) from the different studies included and excluded from the analysis were noted in a tabular form (Table 1, 2). All disagreements were resolved by the third and fourth authors.
Assessment of Risk of Bias in Included Studies
Three authors independently assessed the risk of bias using the risk of bias assessment tool in Review Manager (Revman) Version 5.3 (The Cochrane Collaboration, Oxford, UK, 2014) software. The following points were taken into consideration when assessing if there was adequate sequence generation to rule out selection bias. We examined if the patient group allocation reconcealed adequately to rule out selection bias. We also looked for whether researcher knowledge of the allocated interventions was adequately prevented during the study or not. Participants and personnel blinding was specifically looked for to rule out performance bias. We also looked for the blinding of the outcome assessors to rule out detection bias. We looked for whether incomplete outcome data issue was adequately addressed or not to rule out attrition bias. We also looked at if the reports of the study were free of suggestion of selective outcome reporting to rule out reporting bias. Lastly we also looked for whether the study was apparently free of other problems that could put it at risk of bias. Any disagreements were resolved by the fourth author. The risk of bias has been elaborated in Supplementary Table 1.
Measures of Treatment Effect
For continuous variables, the outcomes were expressed as mean differences (MD). International system (SI) units were used for analysis, and all studies reporting results in conventional units were converted to SI units for analysis. For dichotomous outcomes (treatment success) results were expressed as risk ratios (RR) with 95% confidence intervals (CI). For adverse events, results were expressed as post treatment absolute risk differences. RevMan 5.3 was used to compare MD of the different primary and secondary outcomes between letrozole and the control groups of the included studies.
Assessment of Heterogeneity
Heterogeneity was initially assessed by studying the forest plot generated for the primary and secondary outcomes of this study. Subsequently, heterogeneity was analysed using a chi2 test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I2 test (10). The interpretation of I2 values was as follows: 0% to 40%: might not be important; 40% to 60%: may represent moderate heterogeneity; 60% to 90%: may represent substantial heterogeneity; 90% to 100%: considerable heterogeneity. The importance of the observed value of I2 depends on the magnitude and direction of treatment effects and the strength of the evidence for heterogeneity (e.g. p value from the chi2 test, or a CI for I2) (10).
Grading of the Results
An overall grading of the evidence (certainty of the evidence) related to each of the primary and secondary outcomes of the meta-analysis was done using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (11). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within-trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (11). The GRADEpro Guideline Development Tool software (McMaster University and Evidence Prime Inc, 2015) was used to create the Summary of Findings (SoF) table in this meta-analysis (Table 3). The “certainty of evidence” has been graded into four categories, namely “high” (there is a lot of confidence that the true effect lies close to that of the estimated effect), “moderate” (there is moderate confidence in the estimated effect: The true effect is likely to be close to the estimated effect, but there is a possibility that it is substantially different), “low” (there is limited effect in the estimated effect: The true effect might be substantially different from the estimated effect) and, “very low” (there is very little confidence in the estimated effect: The true effect is likely to be substantially different from the estimated effect) (11).
Publication bias was assessed by plotting the Funnel Plot, which specifically targets small study bias, in which small studies tend to show larger estimates of effects and greater variability than larger studies (9). Presence of one or more of the smaller studies outside the inverted funnel plot was taken as evidence of presence of significant publication bias (Supplementary Figure 1) (12).
Data Synthesis
Data was pooled as a random effect model for the analysis of primary and secondary outcomes. The outcomes were expressed as 95% CI. Forrest plots were plotted with the left side of the graph favouring letrozole and the right side of the graph favouring control using RevMan 5.3 software. A p<0.05 was considered statistically significant.
Results
A total of 357 articles were found after the initial search (Figure 1). Following the screening of the titles, and abstracts, the search came down to 173 articles. Thirty eight duplicates were removed. One hundred and thirty articles were reviewed in details from which seven RCTs which fulfilled all inclusion and exclusion criteria were included in the meta-analysis (Figure 1) (5,6,13,14,15,16,17). One study was removed due to lack of a valid control group (18). Three studies evaluating impact on growth of letrozole in children with precocious puberty were excluded (19,20,21).
Of the seven studies included in this meta-analysis, analysis was done based on the nature of the control group. The control was testosterone in the studies by Kohva et al (2020) (15) and Varimo et al (2019) (5) and hence the results from these studies have been analysed in the ACG. The controls were placebo in the studies by Hero et al (2006) (13), Hero et al (2010) (14), and Wickman et al (2001) (17), and hence the results from these studies have been analysed in the PCG. In the study by Rohani et al (2019) (16), the control group received nothing and hence its results have been analysed in the PCG). The study by Salehpour et al (2010) (6) has three groups comparing the outcomes of children with CGDP receiving letrozle, oxandrolone or placebo. Hence the results of comparison between children receiving letrozole vs oxandrolone in this study has been presented as Salehpour et al 2010a (6) under the ACG. The results of comparison between children receiving letrozole vs placebo in this study has been presented as Salehpour et al 2020b (6) under the PCG.
The details of the studies included in this meta-analysis have been elaborated in Table 1. The studies which were evaluated but were excluded have been summarized in Table 2.
Risk of Bias in the Included Studies
The summaries of risk of bias of the seven studies included in the meta-analysis have been elaborated in Figure 2a, Figure 2b and Supplementary Table 1. Random sequence generation, reporting bias and other bias were judged to be at low risk of bias in all seven studies (100%). Source of funding, especially pharmaceutical, authors from the pharmaceutical organizations and conflict of interests were looked into in the “other bias” section. Allocation concealment bias (selection bias) were judged to be low risk in two studies (28.57%). Performance bias (blinding of participants and investigators) and detection bias (blinding of outcome assessors) were judged to be at low risk of bias in four out of seven studies (57.14%). Attrition bias was judged to be at low risk in six out of seven studies (85.71%).
Effect of Letrozole on Primary Outcomes
Predicted Adult Height
Data from two studies involving 88 children with CDGP was analysed to find out the impact of letrozole on PAH after at least 12 months of treatment, when compared to those receiving testosterone in the control group (ACG). Individuals receiving letrozole had a greater improvement in PAH but was statistically not significant when compared to those in the ACG [MD: 2.21 cm (95% CI: -1.71-6.16); p=0.27; I2=98% (considerable heterogeneity); Figure 3a; moderate certainty of evidence (MCE); Table 3]. Data from three studies involving 84 children with CDGP was analysed to find out the impact of letrozole on PAH after at least 12 months of treatment, when compared to those receiving placebo (PCG). Individuals receiving letrozole had a significantly greater improvement in PAH when compared to PCG [MD: 4.63 cm (95% CI: 3.90-5.36); p<0.01; I2=0% (low heterogeneity); Figure 3b; high certainty of evidence (HCE); Table 3].
Testicular Volume
Data from two studies involving 57 children with CDGP was analysed to find out the impact of letrozole on testicular volume after 6 and 12 months of treatment, when compared to those receiving testosterone in the control group (ACG). After 6 months of treatment, children receiving letrozole had a significantly greater increase in testicular volume when compared to those in the ACG [MD 5.51 mL (95% CI: 2.83-8.18); p<0.01; I2=0% (low heterogeneity); Figure 3c; HCE; Table 3], which persisted even after 12 months of treatment [MD: 3.36 mL (95% CI: 0.58-6.75); p=0.02; I2=0% (low heterogeneity); Figure 3d; HCE; Table 3].
Data from only one study [Wickman et al (2001) (17)] involving 19 children with CDGP was analysed to find out the impact of letrozole on testicular volume after 12 and 18 months of treatment, when compared to those receiving placebo (PCG). Children receiving letrozole had significantly higher testicular volume after 12 months [MD: 4.80 mL (95% CI: 0.57-9.03); p=0.03] but not after 18 months of therapy [MD: 1.90 mL (95% CI: -2.61-6.41); p=0.41], when compared to those receiving placebo.
Effect of Letrozole on Secondary Outcomes
Height Standard Deviation Score
Data from one study [Salehpour et al (6)] involving 61 children was available comparing the changes in Ht-SDS after at least 12 months of therapy in ACG. Data from two studies [Salehpour et al (6) and Rohani et al (16)] involving 65 children were available comparing the changes in Ht-SDS after at least 12 months of therapy in PCG. Children receiving letrozole had a significantly greater improvement in Ht-SDS when compared to those receiving placebo in PCG [MD: +0.63 (95% CI: 0.52-0.74); p<0.01; I2=0% (low heterogeneity)], but not when compared to those receiving testosterone (ACG) [MD: 0.00 (95% CI: -0.16-0.16); p=1.00].
Bone Age
Data from two studies involving 88 children was analysed comparing the changes in BA after 12 months of therapy with letrozole, as compared to those receiving testosterone in the ACG. When compared to ACG, children receiving letrozole has a slower progression in BA, which approached statistical significance [MD: -0.84 years (95% CI: 2.83-8.18); p=0.06; I2=0% (low heterogeneity); Figure 3e; low certainty of evidence; Table 3].
Data from three studies involving 88 children was analysed comparing the changes in BA after 12 months of therapy with letrozole, as compared to those receiving placebo (PCG). When compared to PCG, children receiving letrozole has similar progression in BA [MD: 0.06 years (95% CI: -0.88-0.99); p=0.91; I2=90% (considerable heterogeneity); Figure 3f].
Luteinizing Hormone
Data from two studies involving 55 children with CDGP was analysed to find out the impact of letrozole on serum LH after 6 and 12 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum LH was significantly higher after 6 months [MD: 5.28 IU/L (95% CI: 3.16-7.40); p<0.01; I2=0% (low heterogeneity); Figure 4a], but not after 12 months [MD: 0.05 IU/L (95% CI: -0.69-0.79); p=0.90; I2=0% (low heterogeneity); Figure 4b] of treatment with letrozole, when compared to ACG.
Data from one study [Hero et al 2006 (13)] involving 17 children with CDGP was analysed to find out the impact of letrozole on serum LH after 6 and 12 months of treatment, when compared to those receiving placebo (PCG). Serum LH was significantly higher after 6 months [MD: 6.50 IU/L (95% CI: 3.40-9.60); p<0.01], and 12 months [MD: 5.10 IU/L (95% CI: 2.14-8.06); p<0.01] of treatment with letrozole.
Follicle Stimulating Hormone
Data from two studies involving 55 children with CDGP was analysed to find out the impact of letrozole on serum FSH after 6 and 12 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum FSH was significantly higher after 6 months [MD: 3.59 IU/L (95% CI: 1.42-5.76); p<0.01; I2=0% (low heterogeneity); Figure 4c], but not after 12 months [MD: -0.20 IU/L (95% CI: -1.21-0.61); p=0.63; I2=0% (low heterogeneity); Figure 4d] of treatment with letrozole, when compared to ACG.
Data from one study [Hero et al 2006 (13)] involving 17 children with CDGP was analysed to find out the impact of letrozole on serum FSH after 6 and 12 months of treatment, when compared to those receiving placebo (PCG). Serum FSH was significantly higher after 6 months [MD: 7.70 IU/L (95% CI: 4.37-11.03); p<0.01], and 12 months [MD: 2.70 IU/L (95% CI: 0.42-4.98); p=0.02] of treatment with letrozole.
Testosterone
Data from two studies involving 57 children with CDGP was analysed to find out the impact of letrozole on serum total testosterone after 6 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum total testosterone was significantly higher after 6 months [MD: 22.73 mmol/L (95% CI: 14.96-30.50); p<0.01; I2=0% (low heterogeneity); Figure 4e], treatment with letrozole, when compared to ACG. Data from three studies involving 118 children with CDGP was analysed to find out the impact of letrozole on serum total testosterone after 12 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum total testosterone was not significantly different after 12-24 months [MD: -0.60 mmol/L (95% CI: -2.35-1.15); p=0.50; I2=0% (low heterogeneity); Figure 4f; HCE; Table 3], treatment with letrozole, when compared to ACG.
Data from one study [Hero et al 2006 (13)] involving 17 children with CDGP was analysed to find out the impact of letrozole on serum total testosterone after 6 months of treatment, when compared to those receiving placebo (PCG). Serum testosterone was significantly higher after 6 months [MD: 49.20 mmol/L (95% CI: 22.05-76.35); p<0.01], of treatment with letrozole. Data from three studies [Hero et al 2006 (13), Salehpour et al (6) and Wickman et al (2001) (17)] involving 89 children with CDGP was analysed to find out the impact of letrozole on serum total testosterone after 12 months of treatment, when compared to those receiving placebo (PCG). Serum total testosterone was significantly higher after 12 months [MD: 32.37 mmol/L (95% CI: 10.58-54.16); p<0.01; I2=97% (considerable heterogeneity); MCE; Table 2] treatment with letrozole, when compared to PCG.
Inhibin-B
Data from two studies involving 57 children with CDGP was analysed to find out the impact of letrozole on serum inhibin-B after 6 and 12 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum inhibin-B was significantly higher after 6 months [MD: 62.97 ng/L (95% CI: 24.50-101.43); p<0.01; I2=0% (low heterogeneity); Figure 5a], and 12 months [MD: 25.40 ng/L (95% CI: 1.51-49.29); p=0.04; I2=0% (low heterogeneity); Figure 5b] of treatment with letrozole, when compared to ACG.
Data from one study [Wickman et al (2001) (17)] involving 19 children with CDGP was analysed to find out the impact of letrozole on serum inhibin-B after 5, 12 and 18 months of treatment, when compared to those receiving placebo (PCG). Serum inhibin-B was significantly higher only after 5 months [MD: 64.00 ng/L (95% CI: 27.84-100.16); p<0.01], but not 12 month [MD: 35.00 ng/L (95% CI: -6.01-76.01); p=0.09], and 18 months [MD: -5.00 ng/L (95% CI: -43.46-33.46); p=0.80] of treatment with letrozole, when compared to PCG.
Insulin Like Growth Factor-1
Data from two studies [Kohva et al (2020) (15) and Varimo et al (2019) (5)] involving 57 children with CDGP was analysed to find out the impact of letrozole on serum IGF-1 after 6 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum IGF-1 was significantly lower after 6 months [MD: -11.86 nmol/L (95% CI: -18.08 – -5.64); p<0.01; I2=0% (low heterogeneity)], of treatment with letrozole, when compared to ACG. Data from three studies [Kohva et al (2020) (15) Salehpour et al (6) and Varimo et al (2019) (5)] involving 118 children with CDGP was analysed to find out the impact of letrozole on serum IGF-1 after 12-24 months of treatment, when compared to those receiving testosterone in the control group (ACG). Serum IGF-1 was not significantly different after 12-24 months [MD: -1.24 nmol/L (95% CI: -8.70-6.22); p=0.74; I2=0% (low heterogeneity)] of treatment with letrozole, when compared to ACG.
Data from one study [Wickman et al (2001) (17)] involving 19 children with CDGP was analysed to find out the impact of letrozole on serum IGF-1 after 6 and 12 months of treatment, when compared to those receiving placebo (PCG). Serum IGF-1 was significantly lower after 6 months [MD: -11.30 nmol/L (95% CI: -19.39 – -3.21); p<0.01], and 12 months [MD: -9.00 nmol/L (95% CI: -14.52 – -3.48); p<0.01] of treatment with letrozole, when compared to PCG.
Safety
Data from seven studies (235 children) was analysed to evaluate the impact of letrozole on the occurrence of adverse events [(total adverse events (TAEs) and severe adverse events (SAEs)], over 1-4 years of treatment. The occurrence of TAEs [RR 0.61 (95% CI: 0.17-2.17); p=0.45; I2=0% (low heterogeneity); Figure 6a; HCE; Table 3] and SAEs [RR 1.22 (95% CI: 0.28-5.28); p=0.79; I2=0% (low heterogeneity); Figure 6b; HCE; Table 3] was not statistically different in children receiving letrozole as compared to the control group.
Vertebral deformity and end-plate deformity was investigated in the study by Hero et al 2010 (14). In that study data from 12 children (6 receiving letrozole with testosterone vs 6 receiving placebo with testosterone) was analysed after 4.2 years follow up. The occurrence of vertebral deformity [RR 0.28 (95% CI: 0.01-8.42); p=0.47] and end-plate deformity [RR 0.50 (95% CI: 0.05-5.15); p=0.56] was not statistically different in children receiving letrozole as compared to the control group.
Changes in the BMD Z-scores, before and after therapy was noted in the study by Salehpour et al (6). A significantly lower (improvement) in lumbar spine BMD Z-score [MD: -2.59 (95% CI: -2.88 – -2.30); p<0.01; n=61] and femoral neck BMD Z-score [MD: -2.2 (95% CI: -2.55 – -1.85); p<0.01; n=61] was noted in children receiving letrozole as compared to those receiving testosterone in the control group (ACG). Changes in lumbar spine BMD Z-score [MD: 0.11 (95% CI: -0.35-0.57); p=0.64; n=61] and femoral neck BMD Z-score [MD: 0.10 (95% CI: -0.25-0.45); p=0.58; n=61] was not significantly different when comparing children receiving letrozole to those receiving placebo (PCG).
A small decline in high density lipoprotein-cholesterol (HDL-C) was noted in children receiving letrozole as compared to those receiving placebo in a cohort of 69 patients from two studies [MD: -0.77 mmol/L (95% CI: -2.00-0.47); p=0.22; I2=99% (considerable heterogeneity); Figure 6c], which was however statistically not significant.
Discussion
This is the first meta-analysis to highlight the efficacy and safety of letrozole in children with CDGP. An important observation from this meta-analysis is letrozole use in children with CDGP is associated with a significantly greater improvement in PAH when compared to receiving placebo. This improvement in PAH with letrozole is comparable to the improvements seen with the use of testosterone in CDGP. In accordance with the previous observation, children receiving letrozole had a significantly greater improvement in Ht-SDS when compared to those receiving placebo but not testosterone. Six months and 12 months letrozole use was associated with a significantly greater improvement in testicular volume in CDGP when compared to both placebo and testosterone. All studies used letrozole in dose of 2.5 mg/day for the duration of the study.
Use of letrozole in CDGP was associated with a slower progression in BA when compared to those receiving placebo or testosterone. Serum LH, FSH, total testosterone and inhibin-B were significantly higher after 6 months of use of letrozole in children with CDGP, when compared to those receiving placebo or testosterone. After 12 months of use, the difference for LH, FSH and testosterone persisted only when compared to placebo, but not with regards to those receiving testosterone. Inhibin-B continued to be significantly higher in children receiving letrozole as compared to testosterone after 12 months of use. Serum IGF-1 was significantly lower after 6 months use of letrozole when compared to those receiving placebo or testosterone. Oestrogen has a trophic impact on growth hormone through paracrine effects, which indirectly has a trophic impact on IGF-1 levels (22). Letrozole is an aromatase inhibitor associated with lower oestrogen levels. Testosterone in contrast is aromatized to oestrogen to some extent in the body, having a trophic impact on GH release from pituitary, explaining the higher IGF-1 levels at 6 months (22). Pubertal BA progression is associated with higher IGF-1 levels (23). A lower BA progression may contribute to the marginally lower IGF-1 levels in the first 6 months use of letrozole. It is important to note that this observation is transient and the difference did not persist after 12 months of clinical use. After 12 months use, IGF-1 levels were comparable in children receiving letrozole or testosterone.
This meta-analysis provided reassuring data regarding the long term safety of letrozole use in CDGP. No increased occurrence of TAEs and SAEs were noted with the use of letrozole. The occurrence of vertebral deformities was not significantly increased. No significant decline/change in BMD Z-scores were noted in children receiving letrozole as compared to placebo. Bone health outcomes were better in children receiving testosterone as compared to letrozole because of the anabolic impact of testosterone on BMD. Testosterone is aromatized to estrogen in the body which has a direct impact on increased bone formation (24). A mild statistically not-significant decline in the good cholesterol HDL-C was noted in children receiving letrozole. This is an observation and its impact on long term cardiovascular outcomes needs further evaluation. Advantages of letrozole over testosterone also includes its oral administration in contrast to monthly injections with regards to testosterone.
Conclusion
To conclude, it may be said that this first meta-analysis on the efficacy and safety of letrozole in CDGP, provides us with reassuring data on the good efficacy and tolerability of this molecule on height outcomes and pubertal progression. Letrozole in comparable to testosterone and superior to placebo with regards to improving height outcomes in CDGP. Letrozole tended to show a better slowing effect on BA progression, when compared to both testosterone and placebo. This may have an additional impact on improving height outcomes. Letrozole is superior to both testosterone and placebo with regards to improvement in testicular volume (an important marker of pubertal progression in boys). Letrozole has a better short term impact on hormonal markers of pubertal progression (LH, FSH, testosterone and inhibin-B).
Click for Supplementary Figure 1, Supplementary Table 1 access link: http://glns.co/qvqp6