Aromatase Inhibitors Combined with Growth Hormone: A Cost-effective Last
Chance for Improving BoysÃ¢ÂÂ Stature at the Near-End of Growth?
Pediatric Endocrinology, Hôpital Bicêtre, Paris Saclay University, Paris, France
- *Corresponding Author:
- Pierre Bougnères
Pediatric Endocrinology, Hôpital Bicêtre, Paris Saclay University, Paris, France
Tel: 90 5334934643
Fax: 90 424
E-mail: [email protected]
Received date: March 13, 2017; Accepted date: March 28, 2017; Published date: April 02, 2017
Citation: Bougnères P (2017) Aromatase Inhibitors Combined with Growth Hormone: A Cost-effective Last Chance for Improving Boys’ Stature at the Near-End of Growth? J Clin Mol Endocrinol 2:2. doi: 10.21767/2572-5432.100036
Copyright: © 2017 Bougnères P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Two studies have recently shown a clear benefit of using nonsteroidal
aromatase inhibitors (AIs) in combination with growth
hormone (rhGH) in pubertal boys of very short stature (between
-2.5 and - 3 SDS) who are approaching the end of their growth
[1,2]. AIs have been used in human therapeutics since the
1990s, mostly in adults , to block aromatase by binding to the
heme iron of aromatase, a cytochrome p450 enzyme that
catalyzes the formation of C18 estrogens (estrone and estradiol)
from C19 androgens (androstenedione and testosterone) . In
males, circulating estradiol is derived from direct testicular
secretion (20%) and from peripheral conversion of adrenal or
testicular androgens [5,6].
AIs were proven to be safe, convenient and effective for the
treatment of hormone sensitive breast cancer in women [7,8].
Since the early 2000s, pediatricians have used third generation
non-steroidal AIs - anastrozole and the more potent letrozole- in
several situations. One of the earliest pediatric use of letrozole
has been to slow down the closure of epiphyseal plates in male
adolescents with pubertal delay who are given testosterone to
accelerate their sexual maturation [9-11]. AIs have also been
used in boys who have precocious puberty . They have been
tested in pubertal gynecomastia [13,14], but due to lack of clear
efficacy are not approved in this indication. AIs have also been
used anecdotically by pediatricians in a few rare diseases, such
as congenital adrenal hyperplasia [15,16], Peutz-Jeghers  or
McCune-Albright syndromes [15-18].
Aromatase inhibitors were well tolerated and there were no
withdrawals from any of the trials because of adverse effects.
Only mild and transient elevations of testosterone and decrease
of HDL-cholesterol within the physiological range have been
observed [1,2,14,19,20]. After 2 years of 2.5 mg letrozole in boys
aged 14.2 ± 1 year, mean testosterone level was 30 nmol/L, a
physiological level which was four-fold higher than in placebotreated
boys . Treatment with an aromatase inhibitor tended
to cause a reduction in HDL-cholesterol at end of treatment of
0.26 and 0.47 mmol/L in two trials [11,21].
An increase of hemoglobin level occurred in patients in whom
testosterone was given in addition of AIs, but does not occur if
AIs are used without added testosterone, which stimulates
erythropoiësis . AIs have positive effects on insulin sensitivity , possibly through an increase of fat-free mass.
Vertebral abnormalities, mistakenly thought by a group of early
investigators to be a secondary effect of letrozole , are now
known to be common in untreated short adolescents [2,24-26].
BMD of lumbar vertebrae, the femoral neck, and markers of
bone formation, such as alkaline phosphatase and osteocalcin,
have been assessed in several of the published reports [9,21,27].
The data are reassuring and indicate that as puberty progresses,
bone density increases similarly in subjects receiving AIs and in
controls, with one study even reporting that volumetric BMD of
the lumbar spine increased during AI administration . Thus
the short-term use of AIs has a reassuring track record for safety
in pediatrics. Indeed, more than 250 adolescents treated with AI
for periods of 0.5-3 years have revealed no serious secondary
effects. Given their efficacy and their good safety profile, the
potential for AIs to slow epiphyseal maturation resulting in
longer linear growth has led to their use as an off-label growth
therapy by pediatric endocrinologists .
Between 2004 and 2009, our group used a combination of
rhGH (0.076 mg/kg) and anastrozole in an observational study of
11 adolescents aged 15.2 ± 0.8 yrs who had almost reached their
adult height . Although these adolescents were sexually
mature and had a bone age at wrist of 14.5 ± 0.8 yrs, their
femoral inferior and tibial superior growth plates were not
entirely fused (knee score 2.8 ± 0.4), which qualified them for a
therapeutic attempt. Treatment was pursued as long as growth
rate remained significant, i.e a mean total duration of 19 ± 6
months (6-24 months). Instead of the expected 157.9 ± 3.8cm, a
final height of 168.4 ± 2.6 cm was obtained in adolescents
treated with rhGH and AIs (164.2 ± 5.6 cm in the rhGH alone
group). This observation suggests that treatment with rhGH and
AIs could allow a gain of 8-10 cm in adult height, superior by the
3-4 cm obtained with GH alone.
Comparable results were recently reported in a randomized
study by Mauras et al. in 26 adolescents aged 14 ± 0.2 cm with bone age 12.7 ± 1 years and testosterone levels averaging 2.2 ± 2
ng/ml . The sexual maturation and bone age were less
advanced in these adolescents than in the previous study by ~2
years. Following 24-36 months of combined AIs (letrozole or
anastrazole) and rhGH (0.042 mg/kg) treatment, final height
reached 166.9 ± 6.5 cm after, compared to 164.8 ± 8 cm in those
treated with rhGH alone. No secondary effects were observed, except for a previously observed slight  increase in fat-free
mass, which many adolescents may find desirable.
rhGH given alone in late puberty has a limited benefit on
adult height , while AIs given alone seem to have no
significant effect on adult height .
Combined rhGH and AIs administration seems to have a very
good risk/benefit ratio in boys with [19,27,30] or without 
growth hormone deficiency. On one side, rhGH has now
demonstrated its long-term safety in patients with isolated
growth hormone deficiency, idiopathic short stature or prenatal
growth failure [31,32]. On the other side, the tolerance and
efficacy of AIs makes them an attractive adjunct to rhGH to be
used for growth promotion at the end of male adolescence,
while their use remains precluded in pre-pubertal boys. Since
published results are still restricted to a limited number of
adolescents, larger studies are needed to evaluate the combined
use of GH and AIs. If efficacy and safety are confirmed on a large
scale, short periods (12-24 months) of treatment with combined
rhGH and AI could become a cost-effective mean to increase the
height of male adolescents near the end of their puberty and growth, a time when adult height can be accurately predicted.
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