Advances in Pediatrics 64 (2017) 111–131

ADVANCES IN PEDIATRICS

Alternatives in the Treatment

of Short Stature
Roberto Lanes, MDa,*, Laura G. González Briceño, MDb,1
a
Pediatric Endocrine Unit, Hospital de Clınicas Caracas, Avenida Panteon, San Bernardino,
Caracas, Venezuela; bDepartment of Pediatric Endocrinology, Gynecology and Diabetes, Hopital
Universitaire Necker-Enfants Malades, 149 rue de Sèvres, Paris 75015, France

Keywords

GnRH analogues
Aromatase inhibitors

Human recombinant insulin-like growth factor-1
Metformin

Low-dose androgens

Key points

Gonadotropin-releasing hormone (GnRH) analogues may be useful in the treat-
ment of short children with decreased growth potential due to early puberty in an
attempt to delay pubertal progression.

Aromatase inhibitors may prolong the growth period of short boys in puberty by
inducing slower bone maturation.

RhIGF-1 administration may be useful in the treatment of short children with
growth hormone resistance or growth hormone inactivating antibodies. Its use-
fulness in the treatment of idiopathic short stature has, however, not been proven.

Low-dose androgen therapy positively affects growth velocity, without affecting
the tempo of puberty or final height, when used for short periods of time.

INTRODUCTION
New therapeutic alternatives for the treatment of otherwise healthy short chil-
dren are clearly needed. Although human recombinant growth hormone
(rhGH) treatment of idiopathic short stature (ISS) was approved by the US
Food and Drug Administration years ago, it requires daily parenteral adminis-
tration and its cost remains prohibitive in many parts of the world. Its

Disclosure Statement: The authors have nothing to disclose.

1
Present address: 83 Redpath Avenue, Toronto, Ontario M4S 0A2, Canada.

*Corresponding author. 83 Redpath Avenue, Toronto, Ontario M4S 0A2, Canada. E-mail
address: lanesroberto@gmail.com

http://dx.doi.org/10.1016/j.yapd.2017.03.004
0065-3101/17/ª 2017 Elsevier Inc. All rights reserved.
112 LANES & GONZÁLEZ BRICEÑO

effectiveness is particularly questionable in the case of healthy short children

who enter puberty at a normal but relatively early age, in whom early bone
maturation may lead to decreased lineal growth and growth potential.
In recent years, efforts have been made to find therapeutic alternatives that
will allow for slower bone maturation and for more prolonged spontaneous or
induced growth. In this article, the authors review the effects of gonadotropin-
releasing hormone (GnRH) analogues (GnRHa) alone or in combination with
rhGH and the use of aromatase inhibitors (AIs) on their own or in combination
with rhGH as a means of delaying bone maturation and increasing the final
height (FH) of this group of children.
Endocrine short stature may be due to growth hormone (GH) deficiency of
hypothalamic-pituitary origin. However, it can also be secondary to abnormal-
ities in the GH receptor, anomalies in the signal transduction between GH and
its receptor, to abnormalities in the formation of the ternary complex formed
by insulin growth factor-1 (IGF-1), the acid labile subunit (ALS) and binding
proteins, or to abnormalities of the IGF-1 gene. These situations may lead to
IGF-1 deficiency, which could potentially be treated more effectively with re-
combinant human insulin-like growth factor-1 (rhIGF-1).
Other treatment choices could include low-dose androgen therapy as a
growth-promoting alternative for short peripubertal boys and metformin in
girls who are born small for gestational age (SGA) and who could present
with an increased risk of early adrenarche, early menarche, and therefore, a
premature detention of growth leading to decreased FH.

GONADOTROPIN-RELEASING HORMONE ANALOGUES

During puberty, both growth velocity and epiphyseal fusion accelerate, leading
to the completion of most of the long bone growth. Anomalies in the tempo of
puberty may influence the FH of affected subjects, so that an early exposure to
sexual steroids, as seen in precocious puberty or congenital adrenal hyperpla-
sia, may lead to a reduction in FH, whereas gonadotropin deficiency or estro-
gen deficiency or insensitivity may be associated with prolonged lineal growth
and an increase in FH.
GnRHa administration has been effective in suppressing gonadotropin and
gonadal steroid secretion, resulting in slower bone maturation, delayed bone
fusion, and an increased FH of some children with gonadotropin-dependent
precocious puberty [1–5]. Whether a similar effect can be obtained in short chil-
dren with either a normal timed or an early puberty (EP) remains to be seen.
Initial French studies by Lindner and colleagues [6], Carel and colleagues [7],
and Bouvattier and collaborators [8] demonstrated how the parenteral admin-
istration of the GnRHa triptorelin, at a dose of 3.75 mg per month, transiently
delayed sexual maturation, decreased growth velocity, and retarded bone
fusion. However, its effect on FH remained controversial, as both treated
and untreated subjects were found to be comparable in terms of adult height.
On the other hand, Municchi and colleagues [9] treated children with short stat-
ure and normally timed puberty for a period of 4 years, demonstrating an
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 113

increase in the predicted adult height (PAH) of GnRHa-treated children when

compared with that of placebo (Pl)-treated subjects. These patients, were, how-
ever, not followed to FH. The study by Yanovski and colleagues [10] was
pivotal in demonstrating the effectiveness of GnRHa in this population of pa-
tients. Fifty adolescents with short stature were treated in a double-blind
manner, with either the GnRHa deslorelin at a dose of 4 lg/kg/d (n ¼ 26)
or with Pl (n ¼ 24) for a period of 3.5  0.9 years and followed until they
reached FH (bone age of 16 in girls and of 17 years in boys, with a growth ve-
locity of <1.5 cm/y). GnRHa treatment resulted in an increase of 0.6 standard
deviation score (SDS) in height or 4.2 cm (1.7–6.7 cm) over the initial PAH,
resulting in an improvement of FH in both boys and girls when compared
with that obtained in patients treated with a Pl. However, the increment in
bone mineral density (BMD) during treatment with a GnRHa was decreased,
so that GnRHa-treated adolescents presented with a lumbar BMD of 1.6  1.2
SD below that of the general population (the Pl-treated group had a BMD of
0.3  1.2 SD below that of the general population). The investigators
concluded that although prolonging the growth period through the suppression
of gonadal steroids with a GnRHa resulted in a moderate increase in FH for
most adolescents, the potential benefits of such treatment did not outweigh
the risks. Therefore, GnRHa treatment could not be routinely recommended
to augment height in short adolescents with normally timed puberty.
It is also important to remember that although most of the patients treated
with a GnRHa decrease their growth velocities to a normal prepubertal level,
in many of these subjects, the growth velocity may decrease to levels below
normal, affecting their growth potential. The results of several studies in which
GnRHa therapy was administered to children with short stature and normally
timed puberty can be seen in Table 1.

GONADOTROPIN-RELEASING HORMONE ANALOGUES

COMBINED WITH GROWTH HORMONE
This section reviews the use of a GnRHa in short children with decreased
growth potential due to EP in an attempt to delay pubertal progression, while
at the same time aiming to accelerate their growth velocity through the admin-
istration of rhGH. Results of initial studies using PAH as their main outcome
were contradictory. Although Saggese and colleagues [11] found that combined
treatment with GnRHa and rhGH was effective in increasing the PAH of short
children without GHD and a normally timed puberty, Job and colleagues [12]
concluded that the delay of puberty in children with idiopathic short stature
(ISS) or with constitutional delay of puberty did not result in an improvement
in growth velocity or in adult height prediction (AHP). Controversies also exist
regarding the FH obtained by this group of children following the combined
use of a GnRHa and rhGH. Balducci and colleagues [13] followed a small num-
ber of subjects with short stature and normally timed puberty treated with com-
bined therapy to FH, concluding that although the AHP increased initially, it
did not result in an increase in FH. These findings were similar to those
 114
Table 1
GnRHa use in children with short stature and normally timed puberty
Time of
Population Treatment used treatment Gain in FH Others
Lindner et al [6], 9 girls (11.8  1.5 y) Triptorelin 3.75 mg 2y No significant
1993 8 boys (13.2  1.1 y) intramuscularly improvement of
(IM) monthly predicted adult stature
after 3 y of study
Municchi et al [9], 16 children: 9 Deslorelin 4y Increase in PAH by 7.2 cm 3 children in the treated
1993 treated, 7 Pl 4 lg/kg/d vs Pl compared with baseline group and one in the Pl
prediction, increase by group were also treated
10.9 cm compared with with GH (their exclusion
Pl treated subjects did not affect the results)
Carel et al [7], 31 girls (11.9  1 y) Triptorelin 3.75 mg 23  4 mo Gain in FH: 2.2  2.6 cm
1996 every 4 wk (not significant)
PAH at a bone age of
14.9  1.3 y:
1  2.3 cm greater than
pretreatment PAH, and

LANES & GONZÁLEZ BRICEÑO

1.2  2.2 cm below
PAH at the end of the
treatment
Bouvattier et al [8], 30 girls (8.4–10 y) Triptorelin 3.75 mg 2y FH in treated:
1999 20 treated, 10 Pl IM every 4 wk vs Pl 157.6  4 cm vs
156.1  5.3 cm in Pl
group (no significant
difference)
Yanovski et al [10], 50 children Deslorelin 3.5  0.9 y FH þ0.6 SD (4.2 cm) over
2003 32 girls (12.1  1.3 y) 4 lg/kg/d vs Pl initial PAH, but decrease
and 18 boys in BMD (1.6  1.2
(13.3  1.0 y) SDS)
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 115

obtained by the authors [14] in 10 girls with short stature and relatively EP
treated with combined GnRHa and rhGH therapy for 2.5 years; they did
not improve their PAH and ended up with a FH below their target height
and similar to that of a nontreated control group. On the other hand, Pasquino
and colleagues [15] demonstrated how a group of 12 girls treated with com-
bined therapy increased their FH when compared with their PAH before ther-
apy, with a gain of 10.2  2.9 cm in height. A gain in adult height in 5 patients
with isolated SHOX defects treated with combined rhGH and GnRHa was
also demonstrated by Scalco and colleagues [16], supporting the treatment of
patients with this genetic defect to avoid the loss of growth potential during
puberty.
A more recent study by Van Gool and colleagues [17] allows the reader to
better understand and to more accurately evaluate this form of therapy. Thirty-
two adolescents in puberty Tanner stage II to III, with a bone age of less than
12 years in girls and less than 13 years in boys and with a height and FH pre-
diction of less than 2 SDS, were treated with rhGH and the GnRHa, triptorelin,
administered monthly for a 3-year period. Subjects were followed to FH and up
to a chronologic age of greater than 18 years in girls and greater than 19 years
in boys. Treated patients had a greater initial height gain than those of the con-
trol group, but during subsequent follow-up, they lost 50% of this increase over
PAH, resulting in a moderate increase of only 4.9 cm in their FH. Although
neither their body mass index (BMI) nor their cortical BMD were affected
by treatment, both the areal and the volumetric lumbar spine BMD were lower
in boys treated with combined therapy. The investigators concluded that
because this expensive and intensive treatment regimen resulted in only modest
height gain, and given the possible adverse effect on peak bone mineralization
in boys, rhGH plus GnRHa should not be considered routine therapy for chil-
dren with ISS. The findings of several studies performed with combined ther-
apy can be seen in Table 2.
The authors recently evaluated the effect of combined rhGH and GnRHa
therapy on the near-final height (NFH) of children with ISS in EP [18]. Twenty
patients with ISS were treated with combined therapy, whereas 12 nontreated
children with ISS served as controls. Patients treated with combined therapy
improved both their PAH at 2 years of therapy and their NFH. However, treat-
ment with combined therapy for 2 years did not generate additional benefits
over that obtained with rhGH administration alone (a total increase in PAH
of 7.9  4.9 cm with combined therapy vs 7.3  6.0 cm with rhGH). Total
height gain SDS was also not significantly different between groups.

Possible side effects of gonadotropin-releasing hormone analogue

treatment
The administration of a GnRHa for a short period of time (10 weeks) was
found to be associated with substantial changes in body composition and inter-
mediary metabolism. Mauras and colleagues [19] demonstrated increased
adiposity and decreased rates in protein synthesis, lipid oxidation, energy
 116
Table 2
Combined rhGH and GnRHa treatment in normal children with short stature
Pubertal Dose and duration of Benefit of
Study Age stage treatment Gain in final height association?
Saggese et al [11], 7 girls 11.5  0.95 y Tanner rhGH 0.65  0.07 Increase in PAH of 6.1 cm May be useful
1995 (ISS) Control group (7 2 or 3 IU/kg/wk FH above PAH in 5 girls
untreated girls) (31 lg/kg/d) þ triptorelin
66  9 lg/kg, every 28 d
Treated for 2 y
Job et al [12], 16 boys 14.4  0.8 y Tanner Randomized: PAH slightly but not No
1994 (ISS) and 14 girls 12.2  2 or 3 Group A: rhGH alone (0.1 significantly increased in
1.2 y IU/kg/d)/6 d/wk both groups, gain 2–5 cm
(28.6 lg/kg/d) No advantage of
Group B: rhGH þ triptorelin rhGH þ GnRHa use over
3.75 mg during the first 2 y rhGH alone
Treated for 3 y

LANES & GONZÁLEZ BRICEÑO

Balducci et al [13], 10 girls 11.6  1.4 y Tanner rhGH: 0.1 IU/kg/d/6 d/wk Improvement of PAH at end No
1995 (ISS) 2 or 3 (28.6 lg/ of treatment, but FH is not
kg/d) þ leuprolide acetate significantly different
3.75 mg IM every 25 d compared with PAH at
Treated for 28.1  5.4 mo beginning of treatment
Lanes et al [14], 7 girls and 3 boys Tanner rhGH: No improvement in FH in the No
1998 (ISS) 11.8  1.3 y 2 or 3 0.1 IU/kg/d 6 d/wk treated group
Control group: 7 girls (28.6 lg/
and 3 boys kg/d) þ leuprolide acetate
0.3 mg/kg IM every 28 d
Treated for 2 y
 ALTERNATIVES IN THE TREATMENT OF SHORT STATURE
Pasquino et al [15], 12 girls 10.2  0.9 y Tanner rhGH: 0.3 mg/kg/wk FH 10  2.9 cm above PAH Yes
2000 (ISS) Control group: 12 girls 2 or 3 (43 lg/kg/d) þ triptorelin in combined treatment
10.7  1 y (GH alone) 100 lg/kg every 21 d FH 6.1  4.4 cm above PAH
Treated for 4.6  1.7 y when rhGH alone was
Controls: GH for 4.9  1.4 y used
Van Gool et al [17], 32 adolescents, BA <12 y Tanner rhGH: Net gain in FH of 4.9 cm in Positive but
2007 (SGA/ISS) (girls) or <13 y (boys) 2 or 3 50 lg/kg/d þ triptorelin treated group, compared modest effect
Randomized: 15 treated, 3.75 mg IM every month with controls Possible adverse
17 untreated controls Treated for 3 y effect on peak
bone
mineralization
(particularly
in boys)
Scalco et al [16], 5 patients 11.8  2.1 y Tanner 2 rhGH: 50 lg/kg/d þ FH in treated patients: 1.7 Yes
2010 (SHOX 5 controls untreated leuprolide acetate SDS
deficiency) 3.75 mg IM every month Mean height change:
Treated for 2–4.9 y (rhGH) 1.2  0.4 SDS in
and 1.4–5.8 y (GnRHa) untreated
patients, þ0.6  0.4 SDS
in treated patients
Colmenares et al [18], 20 ISS patients Tanner rhGH: 45 (ISS) or 35 (GHD) ISS: gain of 2.4 SDS in near No
2012 (ISS/GHD) (12.1  1.6 y) and 2 or 3 lg/kg/d, titrated FH with rhGH vs 0.8 SDS
9 GHD patients according to height with combined treatment
(11  2 y) velocity and IGF1 (NS)
Control group: 12 ISS levels þ triptorelin GHD: gain of 1.8 SDS with
and 10 GHD, treated 60 lg/kg IM every 28 d GH vs 0.6 SDS with
with GH alone Treated for 3.6  1.4 y (ISS) combined treatment (NS)
or 5.1  2.2 y (GHD) No advantage of
rhGH þ GnRHa use over
rhGH alone

117
118 LANES & GONZÁLEZ BRICEÑO

expenditure, and muscle strength. A marked increase in urinary calcium loss

and in bone reabsorption following short GnRHa use demonstrated the crucial
role of gonadal steroids on bone mineralization, both in girls and in boys.
The possible deleterious consequences, as it pertains to decreased bone ac-
cretion/bone density of GnRHa treatment on its own or combined with
rhGH, were highlighted above [10,17]. These changes as well as the psycholog-
ical impact of suppressing the timely course of puberty in an already short child
have as of yet not been sufficiently and appropriately evaluated.
Although some studies have suggested that GnRHa treatment may
contribute to an increase in weight, this increase in BMI seems to subside
once therapy is discontinued [20]. Other studies suggest that although these
patients may be overweight at the time of diagnosis, their weight gain is not
exacerbated with the use of analogues [21]. The authors recently performed
a retrospective analysis of 71 girls with either central precocious puberty
(CPP) (n ¼ 37) or EP (n ¼ 34) in order to determine whether their BMI,
obesity/overweight rates, and glucose and lipid concentrations at baseline, dur-
ing GnRHa treatment, and shortly after therapy discontinuation were affected
by treatment [22]. Forty-three children were treated with a GnRHa for at least
2 years, whereas 28 were followed without treatment. The authors found a
high prevalence of obesity and overweight among girls with CPP and EP at
diagnosis, but this risk was greater in girls with CPP. BMI z scores and
obesity/overweight rates remained stable during GnRHa therapy in girls
with CPP and EP and tended to decrease in GnRHa-treated patients once
therapy was discontinued for several months. Weight z scores were higher
at 3 years in treated girls with CPP versus untreated ones. Fasting glucose
and lipids were in the normal reference ranges at the time of diagnosis and re-
mained stable during the 3-year follow-up period, regardless of whether pa-
tients were treated or not.
Long-term GnRHa treatment has been proven to be safe and does not result
in transient or permanent hypogonadism or in infertility. Normal pubertal
development resumes shortly after discontinuation of the analogue in patients
treated with a GnRHa for CPP, with normal menarche occurring months later,
followed by normal fertility rates [23]. There are no reasons to suspect this pro-
cess will not follow this same pattern in patients treated with an analogue for
short stature and EP.
The high cost of GnRHa treatment on its own or in combination with rhGH
has to be considered and discussed with the family, informing them of the need
for intensive parental administration of these medications and for long-term
treatment and follow-up of these short, but otherwise healthy children. Because
of the modest benefits of these medications in improving the FH of short pa-
tients with either early or normally timed puberty and their possible side ef-
fects, therapy has to be individualized, and both patients and their parents
have to be aware of their limitations. What seems to be clear from reviewing
the literature is that for a GnRHa analogue to be effective in improving the
FH of short children, therapy has to be started relatively early (shortly after
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 119

the beginning of puberty, while bone fusion is still not advanced) and has to be
maintained for a considerable period of time, probably for no less than 3 to
4 years.

AROMATASE INHIBITORS
AIs are a class of hormonal drugs that block aromatase, a microsomal P450
enzyme product of the CYP19 gene [24], which catalyzes the rate-limiting
step in the production of estrogens (conversion of testosterone [T] to estradiol
and of androstenedione to estrone). Enzyme activity is present in many tissues,
including the ovary, breast, brain, muscle, liver, and adipose tissue [25]. AIs
have been used for the treatment of estrogen-sensitive breast cancer, endome-
triosis, peripheral precocious puberty, adrenal hyperplasia, and gynecomastia
[26–34]. The treatment of short-statured boys in puberty was considered after
several studies demonstrated the importance of estrogens in bone maturation.
This was highlighted by the reports in 2 young male adults, one with a defect in
the estrogen receptor [35] and the other with an inactivating mutation of the
aromatase gene [36], who were found to have tall stature, incomplete epiphy-
seal fusion despite their advanced pubertal development, and osteopenia. Es-
trogens, both in girls and in boys, are the principal regulators of epiphyseal
fusion, as demonstrated in boys with point mutations of the estrogen receptor
gene or of the aromatase enzyme gene. The development of selective aroma-
tase blockers and of essays that allow for the measurement of very low estrogen
concentrations has allowed for the evaluation of these medications in children
with short stature [37]. First- and second-generation AIs reduce aromatase ac-
tivity by less than 90%, whereas third-generation inhibitors reduce aromatase
activity by more than 98%. Among these third-generation compounds we
can find triozol derivatives such as letrozole (Lz) and anastrozole (Az) that
bind to the active area of P450 aromatase. These third-generation inhibitors
are more potent, have a longer terminal half-life (about 45 hours), and their ab-
sorption is not significantly affected by food. Their oral administration, reason-
able price, and apparent safety make them interesting alternatives in the
treatment of boys with short stature entering into puberty, as they would delay
maturation of the growth plates, allowing for a longer growth period, and ul-
timately result in increased adult height [38].
In 2001, Wickman and colleagues [39], in a randomized, double-blind,
Pl-controlled study, treated boys with constitutional delay of puberty with
T and Pl, or with T and Lz. Boys who decided to wait for the spontaneous pro-
gression of puberty without medical intervention comprised the control group.
Lz effectively inhibited estrogen synthesis and delayed bone maturation. In
18 months, bone age had advanced 1.1  0.8 years in the untreated group,
1.7  0.9 years in the group treated with T þ Pl, but only 0.9  0.6 years
in the Lz-treated group (P ¼ .03). PAH did not change significantly in the un-
treated and in the T þ Pl groups, whereas in the group treated with T þ Lz, the
increase was 5.1  3.7 cm (P ¼ .004). In a subsequent study, this same group
[40] followed patients until NFH. Boys treated with T þ Lz reached a higher
120 LANES & GONZÁLEZ BRICEÑO

mean NFH than did boys on T þ Pl (175.8 vs 169.1 cm, respectively, P ¼ .04).
T þ Lz–treated boys had a greater increment in height SDS over the pretreat-
ment height SDS than did T þ Pl–treated boys (þ1.4 SDS vs þ0.8 SDS,
P ¼ .03).
In studies by Mauras and colleagues [41,42], 52 adolescent boys with GH
deficiency treated with rhGH were randomized to cotreatment with Az or Pl
daily for up to 36 months. Linear growth was comparable between groups;
however, there was a significantly slower increase in bone age advancement
from baseline in the Az group than in the Pl group after 2 years (þ1.8  0.1
vs þ2.7  0.1; P<.0001) and after 3 years (þ2.5  0.2 vs þ4.1  0.1;
P<.0001). This resulted in a net increase in PAH of þ4.5  1.2 cm in the
Az group at 24 months and of þ6.1  1.4 cm at 36 months, as compared
with a 1 cm gain at both time points in the Pl-treated group. Estradiol and
estrone concentrations increased less in the Az group compared with the Pl
group. Safety data, including glucose, plasma lipid concentrations, and BMD,
were comparable between groups.
Hero and colleagues [43] in a double-blind, Pl-controlled study treated 31
boys, aged 9.0 to 14.5 years, with ISS with either Lz, 2.5 mg/d, or Pl, for 2 years.
In the Lz-treated boys, PAH increased by 5.9 cm (P<.0001), and height SDS for
bone age increased by 0.7 SDS (P<.0001), whereas no changes occurred in
these respective measures in Pl-treated boys. Areal BMD of the lumbar spine
and femoral neck, assessed by dual-energy x-ray absorptiometry, increased
in a similar fashion in both groups during the treatment period, whereas
bone mineral apparent density increased only in those taking Lz (median in-
crease 4.3%; P<.009). In pubertal subjects treated with Pl, luteinizing hormone
(LH) levels increased gradually from 0.6 to 2.4 IU/L, whereas a more marked
increase in LH was noted in patients who received Lz (from 1.0 to 4.5 IU/L at
6 months of treatment), remaining elevated during the whole treatment period.
Similar changes were noted in follicle-stimulating hormone (FSH) and T con-
centrations. Estrogen levels remained in the prepubertal range in subjects of pu-
bertal age treated with Lz, whereas they increased gradually in those treated
with Pl. Similar results were more recently found by Rothenbuhler and col-
leagues [44], who in a prospective randomized study compared the effects of
rhGH þ Az versus rhGH alone in a group of 24 healthy adolescent boys
with ISS aged 15.2  1.2 years with serum T levels in the adult range and a
faltering growth velocity (<3.5 cm/y) leading to a PAH of <2.5 SDS. A his-
torical group of ISS adolescents (n ¼ 17) matched for puberty and growth was
used for comparison. Mean treatment duration was 19 months in the
rhGH þ Az group and 11.5 months in the rhGH group. Adult height was
168.4  2.6 cm in the rhGH þ Az group, 164.2  5.6 cm in the rhGH group
(P<.02), and 160.1  2.8 cm in the historical controls. These findings were also
very recently confirmed by Mauras and colleagues [45], who reported that
combination therapy with AIs þ rhGH administered for 24 to 36 months to
pubertal boys with ISS increased their height potential more than that of AIs
or rhGH alone. Free fat mass accrual was greater with combined therapy,
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 121

and measures of bone health showed no detrimental effects following AIs treat-
ment. A double-blind, Pl-controlled study performed in a group of 91 boys with
constitutional delay of puberty and predicted short stature [46] also showed a
significant increase in PAH after 2 years of Lz, as opposed to patients treated
with oxandrolone or Pl.
However, not all studies have demonstrated an increase in the height potential
of ISS subjects following the administration of AIs. Shams and colleagues [47]
recently evaluated the charts of 20 boys with a bone age of 13 and short stature
(height more than 2 SDS below the mean or 2 SDS below midparental height
with rapid pubertal progress) who were treated with Az for 18 to 30 months.
They detected a small, nonsignificant increase in PAH, with no change in height
SDS and a small decrease in bone age/chronological age. Posttherapy PAH was
different from the mean predicted parental target height (MPTH) in all subjects,
with 8 of them achieving an NFH an average 6.7  1.4 cm less than their MPTH
and 1.9  0.9 cm less than the pretherapy PAH.
Although most studies seem to indicate a positive role for AIs in improving
the height of short children in puberty [39–47], few of these studies have fol-
lowed patients to FH [48]. The total number of studied patients has been small,
and only several studies have been performed in a double-blind, Pl-controlled
fashion, so more clinical trials are needed in order to confirm the positive effect
on FH [49].

Possible side effects of aromatase inhibitors

Although estradiol levels diminished significantly in treated individuals, some
subjects presented with gynecomastia during treatment, suggesting an incom-
plete inhibition of aromatase. LH and FSH levels increased significantly during
AIs therapy, resulting in an increase in testicular volume and in T levels. How-
ever, these hormonal imbalances normalized after discontinuing therapy for
several months.
Several issues regarding the long-term safety of AIs in the treatment of short
children need to be evaluated in more detail, such as the effect of estrogen sup-
pression on bone turnover. Lz-treated boys showed an initial increase followed
by a slow decline in the concentrations of the bone resorption urine marker
N-terminal telopeptide of type I collagen, whereas the serum levels of the
bone formation markers, s-P1NP and alkaline phosphatase, remained un-
changed [50]. In contrast, all markers of bone turnover increased significantly
in the Pl-treated boys. Increased concentrations of androgens have been shown
to inhibit osteoclast differentiation and bone resorption in humans as well as in
cultured human osteoclasts, which might be a key in explaining the low bone
resorption markers observed in Lz-treated children. Concerning bone
morphology, asymptomatic or mildly symptomatic vertebral wedge defor-
mities have been described in boys with ISS previously treated with Lz [50].
The effect of AIs on spermatogenesis, spermatic motility, and fertility also
needs consideration. Such concerns are based on the fact that estrogen
receptor-a knockout male mice show progressive impairment of fertility due
122 LANES & GONZÁLEZ BRICEÑO

to loss of the fluid resorptive function in epithelial cells of efferent ductules, re-
sulting in their swelling and swelling of the rete testis [51]. In addition, male
aromatase knockout mice have impaired spermatogenesis at a younger age.
Furthermore, treatment of male monkeys with Lz reduces their sperm count
and quality.
In addition, the effect of AIs on adrenal function needs to be followed as
based on the study of Karmazin and colleagues [52], 25% of Lz-treated adoles-
cents showed asymptomatic biochemical evidence of adrenal suppression
following low-dose adrenocorticotropic hormone testing. Other studies
[46,53] have also reported reduced levels of high-density lipoprotein cholesterol
and fat mass, an observation that requires further follow-up of these parameters
in AIs-treated subjects.

METFORMIN
Multiple factors have been implicated in the regulation of the beginning of pu-
berty and its tempo of progression. Both insulin and leptin seem to play a role
in accelerating this process, and elevated concentrations of these 2 hormones
have been detected in obese girls, in SGA girls, and in those with precocious
pubarche.
Recent studies have postulated that insulin resistance could contribute to the
early beginning and the rapid progression of puberty in girls born SGA. Ac-
cording to this theory, girls who are born SGA and who subsequently present
with a compensatory period of rapid growth could have an increased risk of
early menarche and a premature detention of growth leading to decreased
FH. These girls would not be ideal candidates for GnRHa treatment because
they begin their puberty at a normal, although early age (8–9 years of age),
and they would not be considered for rhGH therapy because they present
with a normal height at the beginning of puberty. In 2 open-labeled, prospec-
tive studies [54,55], 22 low-birth-weight girls with early-normal puberty and
38 SGA girls with precocious adrenarche were randomized to remain untreated
or to receive metformin (850 mg/d) for 36 months. All girls remained untreated
between the end of treatment and 42 months. Metformin treatment resulted in
a longer time lapse from Tanner stage 2 for breast development to menarche
(P<.01; median difference: þ1.0 year), a taller near-adult height (P<.01), and
leaner body composition (P<.001). Metformin was also associated with lower
insulin resistance and leptin and IGF-I levels and higher SHBG and IGFBP-1
levels and with a more favorable lipid profile. BMD and uterine-ovarian
growth were unaffected. The investigators concluded that this data support
the concept that insulin is a major codeterminant of the pubertal tempo and pu-
bertal height gain in girls.
Metformin treatment could therefore potentially increase the FH of SGA
girls and of girls with premature pubarche. However, studies in a larger num-
ber of patients with these abnormalities and possibly also in boys with hyper-
insulinism, central obesity, and EP followed longitudinally will be needed to
confirm these findings.
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 123

INSULIN-LIKE GROWTH FACTOR-1

Commercial availability of rhIGF-1 has added to the choice of agents that can
be used to treat children with short stature. This treatment was approved
in 2005 for use in conditions of severe IGF-1 deficiency (defined by a height
SDS 3, IGF-1 <2.5th percentile for age and sex [EU], or IGF-1
SDS 3 [US], with normal or high GH secretion) due to genetic growth hor-
mone resistance or insensitivity (GHI) [56–63], or in growth hormone defi-
ciency (GHD) with development of anti-GH antibodies. Studies have been
performed to investigate possible benefits from rhIGF-1 therapy in less severe
IGF-1 deficiency, ISS, Noonan syndrome, leprechaunism, diabetes mellitus,
liver disease, neurologic disorders, or injury and critical illnesses. The combi-
nation of rhIGF-1þ recombinant human insulin-like growth factor binding
protein-3 (rhIGFBP-3) [64,65] was commercially available for a short period
of time, but was removed from the market and is no longer available. IGFs
are potent mitogenic agents, and their actions are determined by the availabil-
ity of free IGFs to interact with IGF receptors. The rate of IGF production,
clearance, and degree of binding to the IGFBPs modulates the levels of free
IGFs in a system. The liver is the main source of circulating IGFs even though
there is physiologically important production of IGF-1 in other tissues,
including the growth plate and bone, with various autocrine and paracrine
functions. In serum, most of the IGF-1 is found as a ternary complex, formed
by IGF-1, IGFBP-3, and the glycoprotein known as ALS. Only a small amount
of IGF-1 is carried by IGFBPs as a binary complex, and less than 1% circulates
in the free form. The formation of the ternary complex protects and conse-
quently prolongs the half-life of both IGFBP-3 and IGF-1. The circulating
half-lives of unbound IGFBP-3 and IGF-1 are very short, between 30 and
90 minutes for IGFBP-3 and less than 10 minutes for IGF-1. Conversely,
the half-life of the ternary complex is much longer at approximately 12 hours.
The binding of IGF-1 to IGFBP-3 and ALS maintains IGF-1 in the intravas-
cular space for steady delivery to target tissues, in contrast to the pulsatile
levels of GH. IGFBP-3 not only extends the serum half-life of IGF-1 but has
also a role in its distribution [66,67].
The use of rhIGF-1 for the treatment of ISS is based on the hypothesis that sub-
tle alterations in the signaling pathways of GH-Growth hormone receptor
(GHR) may account for ISS in children who have low IGF-1, but normal GH
levels [68,69]. This premise has been criticized because even mild inability to pro-
duce IGF-1 should be associated with some elevation in GH. Rosenbloom [70]
has suggested that the commercial viability of these medications, beyond rare
growth-hormone resistance due to growth-hormone receptor/postreceptor de-
fects or growth hormone–inactivating antibodies, is based on assumptions not
supported by evidence. IGF-1 deficiency must be detected in the population
that is able to obtain benefits from such replacement, and such benefits should
match or exceed those achieved from treatment with rhGH (its use has also
been questioned by some for the treatment of ISS). In addition, the efficacy
and safety of rhIGF-1 in ISS children still has to be determined.
124 LANES & GONZÁLEZ BRICEÑO

It is possible that the combination of rhGH and rhIGF-1 could increase the
growth response to either hormone used alone [71]; however, this hypothesis
has not yet been evaluated. As stated by Rosenbloom [70], a concern regarding
the use of rhIGF-1 in children with ISS relates to the suppression of GH, which
may lead to a suboptimal growth response, a lack of proliferation of prechon-
drocytes, and a lack in the local release of IGF-1 at the growth plate.

Safety concerns following the use of recombinant human insulin-like

growth factor-1
Infants and children with GHI have episodes of hypoglycemia that may be se-
vere, similar to those seen with severe GHD. Unlike rhGH replacement ther-
apy, which corrects the hypoglycemia of GHD, IGF-1 injection enhances the
risk. IGF-1 decreases hepatic glucose output and increases muscle glucose up-
take, whereas rhGH has the opposite effects. In the largest treatment study, hy-
poglycemia was noted in 49% of subjects, including 5% with seizures [72]. A
somewhat lower frequency of 31% was reported with the use of rhIGF-1/
rhIGFBP-3, although in a smaller and slightly older population observed
over a shorter period of time. However, a more recent study, from the EU In-
crelex Growth Forum Database Registry [73], shows a much lower prevalence
of hypoglycemia with rhIGF-1 treatment, with events being noted in 17.6% of
the patients (2.7% with severe hypoglycemia), with young age and a diagnosis
of Laron syndrome as predictors of its occurrence.
Lipohypertrophy at the injection site, which can reduce growth response,
affects 11% to 30% of patients [72,73] and is related to failure to rotate injec-
tions. Hair growth at the injection site has only been described with rhIGF-
1/rhIGFBP-3. RhIGF-1 has an inotropic effect that results in asymptomatic
tachycardia in all treated patients, which clears after several months of
continued use. Intracranial hypertension or papilledema occurs in w5%
of rhIGF-1-treated subjects. Headache is a frequent observation, but a
Pl-controlled study found no difference in frequency of headaches between
those receiving rhIGF-I or Pl injections.
Lymphoid tissue hypertrophy occurs in approximately 25% of patients. Hy-
poacusis, snoring, and tonsillar/adenoidal hypertrophy that required surgical
intervention has been described in more than 10% of patients. Thirty-five
percent of subjects having regular chest radiographs showed thymic hypertro-
phy [62]. Parotid swelling and facial nerve palsy have also been described.
Anti-IGF-1 antibodies develop in approximately half of the rhIGF-1-treated
patients during the first year, but these have no effect on response to treatment
[62]. Transient elevation of liver enzymes has also been noted [62]. Acromega-
loid coarsening of the face has been noted in many patients, particularly in
those of pubertal age. Both lean mass and fat mass increase with rhIGF-1, in
contrast to the increase in lean body mass and the decrease of body fat noted
with rhGH treatment of GHD. Hyperandrogenism with oligomenorrhea or
amenorrhea, acne, and elevated serum androgens have been described in pre-
pubertal and young adult patients given daily injections of rhIGF1.
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 125

Although the mitogenic effects of long-term therapy with rhIGF-1 in growing

children is unknown, the evidence for a role for IGF-1 in the increased cancer
risk with hypersomatotropism and the evidence for aberrant tissue effects in
rhIGF-1-treated patients indicate the need for long-term follow-up of treated
patients.

LOW-DOSE ANDROGEN THERAPY

Low-dose androgen therapy may be a growth-promoting alternative for short
peripubertal boys. Androgen therapy with either injectable T or low-dose ox-
androlone (1.25–2.5 mg/d) is low in cost and has been shown to increase the
rate of growth by 3.0 to 5.1 cm/y. The use of oxandrolone, which is not metab-
olized to estrogen, is generally preferred, to avoid accelerated estrogen-
mediated epiphyseal fusion. Long-term studies in ISS children have demon-
strated normal pubertal growth and an attainment of adult height equal to or
slightly above the PAH before treatment following oxandrolone administra-
tion, with few side effects. Stanhope and Brooks [74] treated 24 short peripuber-
tal boys with oxandrolone. Before therapy, their heights were below the third
percentile and they had delayed puberty with bone age retardation of 2.4 years.
Oxandrolone increased height velocity from a mean of 3.7 cm/y to 8.1 cm/y,
and this height velocity was maintained after stopping treatment. Testicular
volume and genital hair development progressed normally. The change in
mean height for bone age SDS was small and nonsignificant.
Low-dose T treatment increases short-term growth velocity, without
affecting predicted or FH [75]. Administration of T esters at a dose of 50 to
100 mg/mo intramuscularly for 2 to 3 months positively affects growth velocity
without advancing bone age and at these doses and treatment duration has no
detrimental effect on FAH. This form of therapy does not affect the tempo of
puberty and may provide a positive psychological benefit for treated children.

SUMMARY
New therapeutic alternatives in the treatment of short stature, other than
rhGH, have been tried lately, and although they offer some hope in improving
the FH of affected children, they should not be used outside of research studies
until their effectiveness and safety are further studied. The pros and cons
related to the use of these medications can be seen in Table 3.
In the case of short children whose height could be further limited by EP,
medications that can delay both sexual and bone maturation such as GnRHa
on their own or in combination with rhGH, or other drugs that can prolong
the growth period by inducing slower bone maturation, as is the case of AIs
and possibly also of metformin, have been evaluated. Although a moderate in-
crease in the PAH or even in the FH of children treated with a GnRHa alone or
in combination with rhGH has been obtained, these medications have to be
administered parenterally and in an intensive manner, patients have to be
monitored regularly and for prolonged periods of time, and the medications
are very expensive. In addition, these medications may produce several side
Table 3

126
Pros and cons of several alternative medications used for the treatment of short stature
Treatment Administration Pros Cons
GnRH Intramuscular (once
Well-known treatment, extensive experience
Injection
analogues monthly or once
Possible efficacy in patients with SHOX deficiency (in
High cost
every 3 mo) association with GH)
Psychological impact due to delayed puberty

May increase FH in combination with GH in young
Modest efficacy of GnRHa used alone in terms of FH,
children with very EP except if precocious or very EP

No negative influence on future fertility
No advantage of GH þ GnRHa over GH alone in most
of the studies

May decrease bone accretion/bone density

Possible weight gain
AIs Oral (daily)
Low cost
Controversial results concerning BMD (tendency to lower

Moderate results in terms of FH (controversial) BMD at 24 mo)

No negative effects of estrogen suppression on most
Mild vertebral anomalies
metabolic parameters
Treatment possible only if puberty has started and only in
boys

Concerns regarding future fertility (in discussion)
Metformin Oral (daily)
Possible positive effect on FH in SGA girls and/or pre-
Experience limited to SGA and/or precocious adre-
cocious adrenarche narche in girls (potential use in SGA boys)

LANES & GONZÁLEZ BRICEÑO

Low cost
IGF1 Subcutaneous
Possible strategy in IGF1 deficiency (height <3
Injection, twice daily
(twice daily) SDS þ low IGF1 levels)
Use limited to ISS when IGF1 deficiency

Even though there is a positive effect on FH, results in
Hypoglycemia
SDS gain are less clear than in ISS treated with GH
Safety concerns regarding effects on cell growth

Suboptimal growth in ISS children when compared with
GH

High cost
Oxandrolone Oral (once daily)
Short-term growth acceleration
No impact on FH

Low cost
Use not approved in Europe

Does not affect the tempo of puberty

May provide a positive short-term psychological benefit
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 127

effects, among which diminished bone peak mass formation following the sup-
pression of gonadal steroids may be paramount. AIs, on the other hand, are
administered orally, their price is reasonable, and the increment in PAH
following their use in boys seems to be as good as or better than that seen
with analogue administration. However, the number of patients studied so
far is small, only a few of these studies have been double-blind and
Pl-controlled, and few patients have been followed to FH. It remains to be
seen whether bone mineralization, vertebral morphology, and fertility can be
adversely affected by their use. Metformin is also relatively cheap and is admin-
istered orally, but longer studies in a larger number of patients followed to final
height have to be completed in order to determine its efficacy.
RhIGF-1 administration may be useful in the treatment of short children with
growth-hormone resistance due to growth hormone receptor/postreceptor de-
fects or growth hormone–inactivating antibodies. However, its use for the treat-
ment of ISS is based on the assumption that subtle alterations in the signaling
pathways of GH-GHR may account for ISS in children who have low IGF-1,
but normal GH levels, and this premise is not necessarily supported by evidence.
RhIGF-1 has to be administered subcutaneously and seems to be even more
expensive and less effective in the treatment of ISS than rhGH; its commercial
availability has decreased in the last few years, and its use in ISS may be limited
due to several adverse events that need to be evaluated carefully. Finally, low-
dose androgen therapy may be a temporary growth-promoting alternative for
short peripubertal boys. Androgen therapy with either injectable T or oral oxan-
drolone is low in cost, positively affects growth velocity, seems not to have a
detrimental effect on FAH when used at low doses and for short periods of
time, and may offer some benefit to children psychologically affected by their
short stature.

References
[1] Manasco PK, Pescovitz OH, Hill SC, et al. Six-year results of luteinizing hormone releasing
hormone (LHRH) agonist treatment in children with LHRH-dependent precocious puberty.
J Pediatr 1989;115:105–8.
[2] Oertner KE, Manasco P, Barnes KM, et al. Adult height in precocious puberty after long-term
treatment with deslorelin. J Clin Endocrinol Metab 1991;73:1235–40.
[3] Brauner R, Malandry F, Zantleifer D. Adult height in girls with idiopathic true precocious pu-
berty. J Clin Endocrinol Metab 1994;79:415–20.
[4] Paul D, Conte FA, Grumbach MM, et al. Long term effect of gonadotropin-releasing hormone
agonist therapy on final and near final height in 26 children with true precocious puberty
treated at a median age of less than five years. J Clin Endocrinol Metab 1995;80:546–51.
[5] Lanes R, Soros A, Jakubowicz S. Accelerated versus slowly progressive forms of puberty in
girls with precocious and early puberty. Gonadotropin suppressive effect and final height
obtained with two different analogs. J Pediatr Endocrinol Metab 2004;17:759–66.
[6] Lindner D, Job JC, Chaussain JL. Failure to improve height prediction in short-stature pubertal
adolescents by inhibiting puberty with luteinizing hormone-releasing hormone analogue.
Eur J Pediatr 1993;152:393–6.
[7] Carel JC, Hay F, Coutant R, et al. Gonadotropin-releasing hormone agonist treatment of girls
with constitutional short stature and normal pubertal development. J Clin Endocrinol Metab
1996;81:3318–22.
128 LANES & GONZÁLEZ BRICEÑO

[8] Bouvattier C, Coste J, Rodrigu C, et al. Lack of effect of GnRH agonists on final height in girls
with advanced puberty: a randomized long-term pilot study. J Clin Endocrinol Metab
1999;84:3575–8.
[9] Municchi G, Rose SR, Pescovitz OH, et al. Effect of deslorelin-induced pubertal delay on the
growth of adolescents with short stature and normally timed puberty: preliminary results.
J Clin Endocrinol Metab 1993;77:1334–9.
[10] Yanovski JA, Rose SR, Municchi G, et al. Treatment with a luteinizing hormone-releasing hor-
mone agonist in adolescents with short stature. N Engl J Med 2003;348:908–17.
[11] Saggese G, Cesaretti G, Barsanti S, et al. Combination treatment with growth hormone and
gonadotropin-releasing hormone analogs in short normal girls. J Pediatr 1995;126:
468–73.
[12] Job JC, Toublanc JE, Landier F. Growth of short normal children in puberty treated for 3 years
with growth hormone alone or in association with gonadotropin-releasing hormone agonist.
Horm Res 1994;41:177–84.
[13] Balducci R, Toscano V, Mangiantini A, et al. Adult height in short normal adolescent girls
treated with gonadotropin-releasing hormone analog and growth hormone. J Clin Endocri-
nol Metab 1995;80:3596–600.
[14] Lanes R, Gunzcler P. Final height alter combined growth hormone and gonadotrophin-
releasing hormone analogue therapy in short healthy children entering into normally timed
puberty. Clin Endocrinol 1998;49:197–202.
[15] Pasquino AM, Pucarelli I, Roggini M, et al. Adult height in short normal girls treated with
gonadotropin-releasing hormone analogs and growth hormone. J Clin Endocrinol Metab
2000;85:619–22.
[16] Scalco RC, Melo SSJ, Pugliese-Pires PN, et al. Effectiveness of the combined recombinant
human growth hormone and gonadotropic-releasing hormone analog therapy in pubertal
patients with short stature due to SHOX deficiency. J Clin Endocrinol Metab 2010;95(1):
328–32.
[17] Van Gool S, Kamp GA, Visser-van Balen H, et al. Final height outcome after three years of
growth hormone and gonadotropin-releasing hormone agonist treatment in short adoles-
cents with relatively early puberty. J Clin Endocrinol Metab 2007;92:1402–8.
[18] Colmenares A, González L, Gunczler P, et al. Is the growth outcome of children with idio-
pathic short stature and isolated growth hormone deficiency following treatment with
growth hormone and a luteinizing hormone-releasing hormone agonist superior to that ob-
tained by GH alone? J Pediatr Endocrinol Metab 2012;25(7–8):651–7.
[19] Mauras N, Hayes V, Welch S, et al. Testosterone deficiency in young men: marked alter-
ations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab
1998;83:1886–92.
[20] Chiocca E, Dati E, Baroncelli GI, et al. Body mass index and body composition in adoles-
cents treated with gonadotropin-releasing hormone analogue triptorelin depot for central
precocious puberty: data at near final height. Neuroendocrinology 2009;89(4):441–7.
[21] Palmert MR, Mansfield MJ, Crowley WF Jr, et al. Is obesity an outcome of gonadotropin-
releasing hormone agonist administration? Analysis of growth and body composition in
110 patients with central precocious puberty. J Clin Endocrinol Metab 1999;84(12):
4480–8.
[22] Colmenares A, Gunczler P, Lanes R. Higher prevalence of obesity and overweight without
an adverse metabolic profile in girls with central precocious puberty compared to girls
with early puberty, regardless of GnRH analogue treatment. Int J Pediatr Endocrinol
2014;5:1–7.
[23] Cassio A, Bal MO, Orsini L, et al. Reproductive outcome in patients treated and not treated
for idiopathic early puberty: long-term results of a randomized trial in adults. J Pediatr
2006;149:532–6.
[24] Thompson EA Jr, Siiteri PK. The involvement of human placental microsomal cytochrome
P-450 in aromatization. J Biol Chem 1974;249:5373–8.
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 129

[25] Cavalieri E, Chakravarti D, Guttenplan J, et al. Catechol estrogen quinones as initiators of

breast and other human cancers: implications for biomarkers of susceptibility and cancer
prevention. Biochim Biophys Acta 2006;1766:63–78.
[26] Geisler J, Lonning PE. Aromatase inhibition: translation into a successful therapeutic
approach. Clin Cancer Res 2005;11:2809–21.
[27] Saberi MR, Vinh TK, Yee SW, et al. CYP19 (aromatase) 1-[(benzofuran-2-yl)(phenylmethyl)
pyridine, -imidazole, and -triazole inhibitors: synthesis and biological evaluation. J Med
Chem 2006;49:1016–22.
[28] Brodie AM, Banks PK, Inkster SE, et al. Aromatase inhibitors and hormone dependent can-
cers. J Steroid Biochem Mol Biol 1990;37:327–33.
[29] Bulun SE, Zeitoun K, Takayama K, et al. Estrogen production in endometriosis and use of aro-
matase inhibitors to treat endometriosis. Endocr Relat Cancer 1999;6:293–301.
[30] Feuillan P, Calis K, Hill S, et al. 2007 Letrozole treatment of precocious puberty in girls with
the McCune-Albright syndrome: a pilot study. J Clin Endocrinol Metab 2007;92:2100–6.
[31] Albers N, Jorgens S, Deiss D, et al. McCune-Albright syndrome—the German experience.
J Pediatr Endocrinol Metab 2002;15(Suppl 3):897–901.
[32] Eugster EA, Dimeglio LA, Wright JC, et al. Height outcome in congenital adrenal hyperpla-
sia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 2001;138:26–32.
[33] Cash R, Brough AJ, Cohen MN, et al. Aminoglutethimide (Elipten-Ciba) as an inhibitor of
adrenal steroidogenesis: mechanism of action and therapeutic trial. J Clin Endocrinol Metab
1967;27:1239–48.
[34] Plourde PV, Reiter EO, Jou H-C, et al, Members of the AsraZeneca Gynecomastia Study.
Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a random-
ized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:4428–33.
[35] Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-
receptor gene in a man. N Engl J Med 1994;331:1056–61.
[36] Morishima A, Grumbach M, Simpson E, et al. Aromatase deficiency in male and female sib-
lings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol
Metab 1995;80:3689–98.
[37] Faglia G, Arosio M, Porretti S. Delayed closure of epiphyseal cartilages induced by the aro-
matase inhibitor anastrozole. Would it help short children grow up? J Endocrinol Invest
2000;23:721–3.
[38] Dunkel L. Use of aromatase inhibitors to increase final height. Mol Cell Endocrinol
2006;254-255:207–16.
[39] Wickman S, Sipila I, Ankarberg-Lindgren C, et al. A specific aromatase inhibitor and poten-
tial increase in adult height in boys with delayed puberty: a randomised controlled trial. Lan-
cet 2001;357:1743–8.
[40] Hero M, Wickman S, Dunkel L. Treatment with the aromatase inhibitor letrozole during
adolescence increases near-final height in boys with constitutional delay of puberty. Clin En-
docrinol 2006;64:510–3.
[41] Mauras N, Welch S, Rini A, et al. An open label 12-month pilot trial on the effects of the aro-
matase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent
boys. J Pediatr Endocrinol Metab 2004;17:1597–606.
[42] Mauras N, Gonzalez de Pijem L, Hsiang HY, et al. Anastrazole increases predicted adult
height of short adolescent males treated with growth hormone: a randomized placebo-
controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 2008;93:
823–31.
[43] Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase
inhibitor increases predicted adult height in boys with idiopathic short stature: a random-
ized controlled trial. J Clin Endocrinol Metab 2005;90:6396–402.
[44] Rothenbuhler A, Linglart A, Bougnères P. A randomized pilot trial of growth hormone with
anastrozole versus growth hormone alone, starting at the very end of puberty in adolescents
with idiopathic short stature. Int J Pediatr Endocrinol 2015;2015(1):4.
130 LANES & GONZÁLEZ BRICEÑO

[45] Mauras N, Ross JL, Gagliardi P, et al. Randomized trial of aromatase inhibitors, growth hor-
mone or combination in pubertal boys with idiopathic short stature. J Clin Endocrinol Metab
2016;101:4984–93.
[46] Salehpour S, Alipour P, Razzaghy-Azar M, et al. A double-blind, placebo-controlled com-
parison of letrozole to oxandrolone effects upon growth and puberty of children with consti-
tutional delay of puberty and idiopathic short stature. Horm Res Paediatr 2010;74:428–35.
[47] Shams K, Cameo T, Fennoy I, et al. Outcome analysis of aromatase inhibitor therapy to in-
crease adult height in males with predicted short adult stature and/or rapid pubertal prog-
ress: a retrospective chart review. J Pediatr Endocrinol Metab 2014;27(0):725–30.
[48] Turpin AL, Popovic J, Karmazin A, et al. Aromatase inhibitor may delay skeletal maturation
and improve final adult height in females [abstract]. Endocr Soc 86th Annu Meet
2004;120:OR32–5.
[49] Audı́ Parera L. Inhibidores de la aromatasa: ¿pueden mejorar el crecimiento esquelético?
Endocrinol Nutr 2009;56:215–7 [in Spanish].
[50] Hero M, Mäkitie O, Kröger H, et al. Impact of aromatase inhibitor therapy on bone turnover,
cortical bone growth and vertebral morphology in pre- and peripubertal boys with idio-
pathic short stature. Horm Res 2009;71:290–7.
[51] Eddy EM, Washburn TF, Bunch DO, et al. Targeted disruption of the estrogen receptor gene
in male mice causes alteration of spermatogenesis and infertility. Endocrinology 1996;137:
4796–805.
[52] Karmazin A, Moore WV, Popovic J, et al. The effect of letrozole on bone age progression,
predicted adult height, and adrenal gland function. J Pediatr Endocrinol Metab 2005;18:
285–93.
[53] Wickman S, Saukkonen T, Dunkel L. The role of sex steroids in the regulation of insulin sensi-
tivity and serum lipid concentrations during male puberty: a prospective study with a P450-
aromatase inhibitor. Eur J Endocrinol 2002;146:339–46.
[54] Ibañez L, Valls C, Ong K, et al. Metformin therapy during puberty delays menarche, pro-
longs pubertal growth, and augments adult height: a randomized study in low-birth-
weight girls with early-normal onset of puberty. J Clin Endocrinol Metab 2006;91:
2068–73.
[55] Ibañez L, Ong K, Valls C, et al. Metformin treatment to prevent early puberty in girls with
precocious pubarche. J Clin Endocrinol Metab 2006;91:2888–91.
[56] Woods KA, Camacho-Hubner C, Savage MO, et al. Intrauterine growth retardation and
postnatal growth failure associated with deletion of the insulin-like growth factor I gene.
N Engl J Med 1996;335:1363–7.
[57] Kofoed EM, Hwa V, Little B, et al. Growth hormone insensitivity (GHI) associated with a STAT-
5b mutation. N Engl J Med 2003;349:1139–47.
[58] Walter JL, Van Wyk JJ, Underwood LE. Stimulation of statural growth by recombinant insulin-
like growth factor 1 in a child with growth hormone insensitivity syndrome (Laron type).
J Pediatr 1992;121:641–6.
[59] Guevara-Aguirre J, Vasconez O, Martinez V, et al. A randomized double-blind, placebo-
controlled trial of safety and efficacy of recombinant insulin-like growth factor-I in children
with growth hormone receptor deficiency. J Clin Endocrinol Metab 1995;80:1393–8.
[60] Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. Two-year treatment of GH receptor
deficiency (GHRD) with recombinant insulin-like growth factor-I in 22 children: comparison
of two dosage levels and to GH treated GH deficiency. J Clin Endocrinol Metab 1997;82:
629–33.
[61] Backeljauw PF, Underwood LE. Therapy for 6.5-7.5 years with recombinant insulin-like
growth factor 1 in children with growth hormone insensitivity syndrome: a clinical research
center study. J Clin Endocrinol Metab 2001;86:1504–10.
[62] Chernausek SD, Backeljauw PF, Frane J, et al. Long-term treatment with recombinant IGF-I in
children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol
Metab 2007;92(3):902–10.
ALTERNATIVES IN THE TREATMENT OF SHORT STATURE 131

[63] Kemp SF. Insulin-like growth factor-I deficiency in children with growth hormone insensitivity:
current and future treatment options. BioDrugs 2009;23:155–63.
[64] Löfqvist C, Niklasson A, Engström E, et al. A pharmacokinetic and dosing study of intrave-
nous insulin-like growth factor-I and IGF-binding protein-3 complex to preterm infants. Pe-
diatr Res 2009;65:574–9.
[65] Rosenbloom AL. Recombinant human insulin-like growth factor-I (rhIGF-I) and rhIGF-I/rhIGF-
I-binding-protein-3: new growth treatment options? J Pediatr 2007;150:7–11.
[66] Khosravi J, Diamandi A, Bodani U, et al. Pitfalls of immunoassay and sample for IGF1: com-
parison assay methodologies using various fresh and stores serum samples. Clin Biochem
2005;38:659–66.
[67] Katz LEL, DeLeon DD, Zhao H, et al. Free and total insulin-like growth factor (IGF)-1 levels
decline during fasting: relationships with insulin and IGF-binding protein-1. J Clin Endocri-
nol Metab 2002;87:2978–83.
[68] Attie KM, Carlsson LM, Rundle AC, et al. Evidence for partial growth hormone insensitivity
among patients with idiopathic short stature. The National Cooperative Growth Study.
J Pediatr 1995;127:244–50.
[69] Goddard AD, Dowd P, Chernausek S, et al. Partial growth-hormone insensitivity: the role of
growth-hormone receptor mutations in idiopathic short stature. J Pediatr 1997;131:S51–5.
[70] Rosenbloom AL. Is there a role for recombinant insulin-like growth factor-I (rhIGF-I) in the
treatment of idiopathic short stature? Lancet 2006;368:612–6.
[71] Janssen JAMJL. Advantages and disadvantages of GH/IGF-I combination treatment. Rev En-
docr Metab Disord 2009;10:157–62.
[72] Backeljauw PF, Underwood LE, GHIS Collaborative Group. Therapy for 6.5–7.5 years with
recombinant insulin like growth factor I in children with growth hormone insensitivity syn-
drome: a clinical research center study. J Clin Endocrinol Metab 2001;86:1504–10.
[73] Bang P, Polak M, Woelfle J, et al, on behalf of the EU IGFD Registry Study Group. Effective-
ness and safety of rhIGF-1 therapy in children: the European Increlex Growth Forum Data-
base Experience. Horm Res Paediatr 2015;83:345–57.
[74] Stanhope R, Brooks CG. Oxandrolone in low dose for constitutional delay of growth and
puberty in boys. Arch Dis Child 1985;60(4):379–91.
[75] Richman RA, Kirsch LR. Testosterone treatment in adolescent boys with constitutional delay in
growth and development. N Engl J Med 1988;319:1563–7.