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- Review -
Treatment of central precocious puberty by GnRH analogs:
long-term outcome in men
Silvano Bertelloni1, Dick Mul2
1Adolescent Medicine, Department of Obstetrics, Gynecology and Pediatrics, Santa Chiara University Hospital, Pisa
56125, Italy
2Leiden University Medical Center, Department of Paediatrics. PO Box 9600, 2300 RC Leiden, the Netherlands
Abstract
In boys, central precocious puberty (CPP) is the appearance of secondary sex characteristics driven by pituitary
gonadotropin secretion before the age of 9 years. In the last years, relevant improvements in the treatment of CPP
have been achieved. Because CPP is rare in boys, the majority of papers on this issue focus on girls and do not
address specific features of male patients regarding end results and safety.
In the present paper, recent advances of CPP management with GnRH analogs in men are summarized. End results in untreated and treated patients are also
reviewed by an analysis of the recently published literature on treatment of CPP in
men. The available data indicate that therapy with GnRH analogs can improve final height into the range of target height without significant adverse
short-term and long-term effects, but longer follow-up of larger series of patients is still required to draw definitive
conclusions. (Asian J Androl 2008 Jul; 10: 525_534)
Keywords: adolescent; male; central precocious puberty; gonadotropin-releasing hormone analog treatment; gonadotropin-releasing
hormone analog safety; long-term outcome; adult height
Correspondence to: Dr Silvano Bertelloni, Adolescent Medicine, Department of Obstetrics, Gynecology and Pediatrics, Santa Chiara
University Hospital, Via Roma, 67, Pisa 56125, Italy.
Tel: +39-050-992-743 Fax: +39-050-888-622
E-mail: s.bertelloni@med.unipi.it
Received 2008-01-07 Accepted 2008-01-30
DOI: 10.1111/j.1745-7262.2008.00409.x
1 Introduction
Central precocious puberty (CPP) is a distinct pediatric disease that can have important physical and
psycho-social consequences [1, 2]. In boys, it occurs when a gonadotropin dependent onset of puberty starts before the age
of 9 years [2]. CPP is due to identifiable organic disorders of the central nervous system (such as tumors, infections,
trauma or radiation) or can be idiopathic [2]. The former is more frequent in men and the latter in women (Table 1).
Currently, gonadotropin-releasing hormone (GnRH) analogs are the drugs of choice for treatment of CPP [1, 3,
4]. In fact, these drugs are able to modify the natural course of CPP, restoring growth potential in treated patients, at
least as has been demonstrated in girls [1, 3, 4]. However, because CPP is less common in boys than in girls (Table 1)
[2, 5_10], very little data is available on the long-term efficacy and safety of GnRH analog treatment in men with CPP.
Therefore, we review the published literature on the long-term outcomes of boys affected by CPP, both treated
and not treated by GnRH analogs and provide a brief overview on the efficacy and safety of GnRH analogs treatment
in this sex.
2 Clinical consequences of central precocious puberty in untreated boys
Historical data on untreated boys with CPP shows
that the main long-term consequence is reduced adult
height; in fact untreated male patients show a final height
of approximately _3 standard deviations below the mean
for their reference values (Table 2) [5, 11_13]. The
attained adult height in men results in a height at least _1
standard deviation score below the mean final height in
women with untreated CPP (Table 2) [5, 11_13],
suggesting a poorer long-term auxological outcome in boys
in comparison with girls. However, historical series have
not taken into account the secular trend in height increase
or might have overrepresented cases that are more
severe than the average patient in series investigated today
[15, 16]. In the past 10 years, we had the opportunity to
collect data on the final height of untreated children with
CPP because parents did not consent to therapy or
delayed diagnosis. Both boys and girls appeared to have a
reduced final height and this was very close to the height
reported in historical series of untreated subjects
(Table 2). Although our groups of untreated male and
female patients were small in size, these data seem to
suggest that the secular trend for an increased height
does not lead to an improvement of the statural outcome
in untreated men with CPP.
Other concerns related to CPP are altered body
proportions in adulthood, with an upper: lower ratio > 1 [1],
psycho-social distress in childhood (decreased peer
interaction, social withdrawal, impairment in school
performance, altered behavioral development, increased
aggression, and increased risk of sexual abuse), and early
engagement in risk-taking behavior (such as smoking,
alcohol or drug abuse, and early unprotected sex) [1, 2,
17], but these items have been poorly documented in
boys.
3 Treatment strategies for central precocious
puberty
Management of CPP should be primarily directed at
the treatment of the underlying cause, when this is
possible [1, 2]. Therefore, surgery and radiation therapy
could be indicated for the various tumors causing
organic CPP [2].
A study comparing surgical resection to medical
treatment with GnRH analogs in patients with hypothalamic
hamartomas, a main cause of organic CPP in men [2, 8,
9, 10], indicates that medical treatment is more
efficacious in suppressing puberty and reducing bone age
progression than surgical therapy [18]. In addition,
long-term follow-up studies demonstrate the non progressive
nature of hypothalamic hamartomas in boys as well as in
girls [19, 20].
In boys, as in girls, with no treatable organic cause,
medical treatment is advisable [1, 2, 4, 15]. The goal
of treatment is the attainment of effective and selective
suppression of gonadal sex steroid secretion to stop
premature sexual maturation [2, 4]. In addition,
treatment should permit the attainment of an adult height
adequate for each individual in relation to his or her
genetic determinants by suppressing the accelerated
skeletal maturation to a larger extent than growth
velocity [1]. Prompt reversal of the suppression after the
discontinuation of treatment, the absence of toxicity
and/or side effects during long-term administration and of
inferences with reproductive function in adulthood are
important considerations in prescribing medical therapy
for CPP [2, 3].
GnRH analogs are the drugs of choice for the
medical therapy of CPP [1_4, 15]. These drugs are synthetic
analogs of the natural decapeptide, in which chemical
substitutions at positions 6 and 10 of the GnRH molecule
increase the resistance to enzymatic degradation and
increase the affinity to the receptor on pituitary
gonadotropes, leading to a desentisization of GnRH receptor and,
consequently, inhibition of the release of luteinizing
hormone (LH) and follicle stimulating hormone (FSH) by
the pituitary gland with a subsequent decrease in gonadal
steroids [3, 21]. Some available GnRH analogs show a
potency varying from 20 up to 200 times that of natural
hormones, with prolonged action and low toxicity [3,
21]. The main commercial formulations of GnRH analogs used in the treatment of CPP in boys are
summarized in Table 3. Administration forms and doses are
also reported in Table 3. The same drugs are used more
extensively in girls because of the higher incidence of
CPP in this sex [1_4].
Depot formulations are usually used (Table 3) [3, 4,
21], because compliance with the daily formulations (nasal
or subcutaneous) is frequently problematic [1].
In Europe, triptorelin depot is widely used at 28 day
intervals [15, 22_25], even though some authors have
reported shorter frequency intervals of administration
(21_26 days) [26_28]. It is usually administered at a dose of
3.75 mg (approximately 60_75 μg/kg) for children
weighting more than 20 kg [22_25]; a half dose has been
employed in patients weighting less than 20 kg [23]. Some
authors have used higher doses (90_100 μg/kg) [28,
29].
Leuprorelin depot is used at different doses in
Europe (3.75 mg/28 days) [30] and in the USA
(7.5_15 mg/28 days) [31, 32]. In Japan, the described doses
range from 10 to 90 μg/kg/28 days [33, 34]. So, the
minimal effective dose required to achieve complete
pituitary desensitization remains a issue for debate. Indeed,
some data indicate that even the higher 7.5 mg monthly
dose may still be inadequate in some children with CPP
[35], which may even exacerbate the disease
progression [3]. In addition, the majority of the trials have
reported data only in girls [31_35].
Results on goselerin depot are mainly from the United
Kingdom and limited to girls [36, 37].
Few papers have explored the new 3-month GnRH analog depot preparations in CPP; they have been done
mainly in girls, while very few data are available in boys
with CPP [36_42]. Recently, data in 3 boys treated
with the new 12 month histrelin subdermal implant
(average release 65 mg/day) in a phase III prospective
study (1 year duration) have been published; they showed
suppression of testosterone levels throughout the study
period [43].
Prospective studies comparing the efficacy and the
safety of the different formulations in boys are lacking
and the choice among the various GnRH analogs remains
somewhat arbitrary, depending on personal experience,
local practices or different regulation of prescription in
various countries more than on evidence-based studies
designed to address the pharmacokinetics and the
pharmacodynamics of GnRH analogs in the children of the
two sexes.
4 End results in boys with central precocious
puberty treated by GnRH analog
The data on adult height in boys with CPP treated by
GnRH analogs are summarized in Table 4. Although the
published studies showed variable end results, adult height
was improved in all the studies (Table 4) in comparison
with the height of untreated boys (Table 2) [5, 11_13].
An increase in final height over pre-treatment predicted
height has been shown in the majority of the studies, but
there is a large variability between the populations
stu-died (Table 4).
In a study from the USA, an increased near final
height in six boys treated with various GnRH agonist
regimens in comparison with the height predicted before
therapy is reported by Paul et al. [13]; boys treated
before the chronological age of 5 years had a better height
gain (Table 4); however, the group remained
approximately 8.5 cm below target height [13]. In an other US
study, Oerter-Klein et al. [10] report on 18 boys with
CPP, the majority affected by a non-idiopathic form,
treated with daily deslorelin administration. Final height
remained lower than mid-parental height, but was
significantly greater than pre-treatment predicted height
(Table 4) [10].
In Europe, the 11 boys reported by Galluzzi et
al. [24], all with idiopathic CPP and treated with triptorelin
depot, showed a final height exceeding the initial
prediction by 6.7 cm and were close to target height (Table 4).
In subsequent studies from Europe, Israel, and India, all
using triptorelin depot, the adult height was greater than
the target height [23, 44_46]. In some reports, some
patients were treated with more than one drug and final
height ranged from 1.8 to 8.2 cm below the target height
[27, 29, 45]. In effect, a significant height gain in
comparison with predicted adult height before the start of
treatment was observed in all but one of these studies
(Table 4).
In Japan, Tanaka et al. [34] described 13 boys treated
with leuprorelin depot for a mean period of 4.1 years;
they reached a mean final height that was _4.4 cm
below the mean target height [34]; in this study height gain
in comparison with predicted adult height before therapy
showed a poor outcome (Table 4).
The relative discrepancies among the various studies
might be due, at least in part, to the small number of
boys enrolled in each trial, the heterogeneity of the
patients treated in terms of auxological characteristics at
the start of treatment, age at start of therapy, the
percentage of idiopathic versus organic forms, and the
different drugs and doses [16, 45]. In addition, the
discrepancies and the negative height gains in some reports
(Table 4) might reflect the difficulties in assessing "height
gain", based on predicted height at the onset of puberty
and the overestimation of the true final height in this
disorder by the Bayley and Pinneau method used in such
studies [16, 47]. Indeed, very little data on the validity
of prediction methods based on bone age in boys with
CPP is available [15, 16, 44].
To address some of these issues, a European
multicentric study was undertaken of the largest series of boys
with CPP treated by a standardized GnRH agonist
regimen (triptorelin depot, 3.75 mg every 28 days) [16]. This
study clearly demonstrated a final height not significantly
different from the target height (Table 5) [16]. In
addition, the boys who started treatment before the age
of 6 years had a significantly better height gain in
comparison with those who started therapy after that age
(Table 5), but final height was not significantly different
between the two groups and both reached their genetic
target (Table 5). Therefore, although the height gain is
better in the patients who are younger at the start of
GnRH therapy, older boys can benefit from treatment as
well [16]. The European multicentric study, including a
similar number of patients affected by organic or
idiopathic CPP, also showed that from the boys treated with
triptorelin depot those with organic CPP attained a lower
final height than boys with idiopathic CPP (Table 5). In
addition, whereas the boys with idiopathic CPP attained
an adult height equal to their genetic target, the patients
with organic CPP had a final height significantly below
their target (Table 5) [16]. The poorer end-results have
been recorded in 5 boys affected by type I
neurofibromatosis, a condition which can impair growth per se
[48]. Therefore, the cause of CPP should be taken into account in
evaluating the long-term efficacy of GnRH analog therapy in
boys with CPP. The large standard deviation of some
parameters and total height gain in particular (Table 5)
can depend on problems related to the method of height
prediction (see above) and the retrospective nature of
the study, the regional differences in practices, on the
use of more (or less) liberal criteria to initiate GnRH
analog treatment, and on the different interval between the
onset of puberty and the start of treatment in the
participating countries [16].
5 Optimization of GnRH analog therapy
The GnRH analog treatment is likely not required for
all children with early onset of puberty. In fact, a "slow
progressive variant" has been described in both boys and
girls [44, 49], which, without any treatment, does not
affect adult height [44, 49_51].
Although there is no general consensus on the
indication for treatment [1], tentative criteria to select boys
with CPP who are candidates for therapy are summarized in Table 6, but it should be kept in mind that clinical
follow up is mandatory in all boys with precocious onset
of pubertal development, independently from the
decision to initiate therapy or not, to ensure the best outcome.
Regarding the discontinuation of therapy, it appears
that bone age at the end of treatment correlates
negatively with height gain after GnRH analog therapy in girls
[1, 23_25, 51, 52]. Indeed, it is reasonable to believe
that stopping therapy at an age close to the median
physiological age of puberty could improve final height [15,
25, 52]; some authors have reported that longer
treatment duration is associated with greater final height
independent of age at discontinuation of treatment [10].
In boys, post-treatment growth is highly correlated with
bone age at discontinuation of treatment [16]. In boys
with normal onset of puberty height, velocity peaks
around the chronological age of 13.5_14 years [14]; the
discontinuation of treatment at a bone age close to peak
height velocity might improve adult height [24].
6 Long-term safety of GnRH agonist treatment in
boys
Very little data is available on the long-term safety on
GnRH analog treatment in boys in terms of reproductive
function, body composition and bone health (which have
been better explored in girls) [1]. The outcomes of
untreated boys are largely unknown, too, so, comparison
between treated and untreated subjects is impossible.
Manasco et al. [53] report on serum testosterone
levels in four boys with organic CPP, showing that
serum hormone concentrations significantly increased and
reached values similar to the pre-treatment period only
3 months after the cessation of GnRH analog therapy.
One year after discontinuation, serum testosterone
levels were in the normal adult range [53]. In the same
study, testis volume increased 3 months after the
discontinuation of treatment and reached the pre-treatment
value after 1 year [53]. Thereafter, the same group [19]
reported on the development of testicular volume after
the discontinuation of therapy in 11 boys, treated for a
mean of 8.8 years with GnRH analogs for CPP due to
hypothalamic hamartoma. The authors showed a progressive increase of testicular volume values not
significantly different from those of 6 controls with normal
onset of puberty [19]. Serum testosterone and
gonadotrophins rose to the normal range approximately 1 year
after discontinuation of treatment and levels were not
significantly different from normal values thereafter.
An Italian study described the reproductive axis in
nine late adolescent men with CPP treated with the GnRH
analog triptorelin depot for a mean period of 5.6 years
(44.4% with idiopathic CPP and 55% with organic CPP)
[27]. Full pubertal development and normal testicular
volume (_0.4 ± 1.1 SDS) was found [27]. The values
of LH, testosterone, FSH and inhibin B were into the
normal adult range [27]. Sperm analysis, performed in 6
patients, showed results to be normal for age, as well
[27]. In these patients, no alteration of testicular
structure was detected by ultrasound scanning of the testes
(unpublished data), whereas 2 out of 11 patients (18%)
reported by Feuillan et al. [19] developed a sonographic
pattern suggestive of testicular microcalcifications
during GnRH analog therapy. Combining our data with that
of Feuillan et al. [19], a prevalence of 10% results, which
is approximately fourfold the prevalence demonstrated
in large young male asymptomatic populations [54].
Albeit the clinical significance of ultrasound imaging for
testicular microcalcifications in subjects without any other
risk factors for testicular neoplasia is still unclear [54,
55], some data suggest a possible association with
testicular cancer [56]. Thus, additional studies on this
aspect should be undertaken.
Being overweight is reported as a long-term concern
of GnRH analog therapy in girls with CPP [57, 58]. In
boys, Palmert et al. [59] demonstrate that the body mass
index (BMI) is above the 85 percentile in approximately
50% of the GnRH analog-treated boys at discontinuation
of therapy, but 71% of these patients were above the 85
percentile already before therapy [59]. Other authors
exploring BMI in girls with idiopathic CPP conclude that
these patients are frequently obese at the onset of GnRHa
therapy and that their obesity is neither long-lasting nor
related to GnRH analog administration [57, 59, 60].
Recently, we explored body composition by dual energy
X-ray densitometry in a group of girls treated by GnRH
analogs after the attainment of adult height and found a
reduced lean body mass and increased fat mass, while
BMI remained unchanged in comparison with values
before therapy, suggesting that patients with CPP treated
with GnRH analog had slightly more body fat in late
adolescence [61], and similar studies will be done in boys.
Regarding the effects on the GnRH analogs on bone
mineralization, some authors suggest that the long-term
suppression of pituitary-gonadal axis in children might
decrease bone mineral density (BMD), possibly
impairing the acquisition of peak bone mass [62_64]. While
no data have been published on the development of BMD
in boys with CPP from the beginning of GnRH analog
treatment, normal lumbar areal and volumetric BMD have
been reported in a small group of men after attainment
of final height [27], suggesting no long-term adverse
effects of the therapy on peak bone mass [1, 28, 62].
7 Conclusions
In summary, CPP and its treatment in men have been
so far poorly evaluated. Available studies indicate that
long-term treatment with GnRH analogs increases final
height into the target height range in the majority of boys
with CPP. Younger patients and those with idiopathic
CPP are likely to receive greater benefit from treatment,
whereas boys with organic forms might have poorer long-term height prognosis. Better end results have been
reported with triptorelin depot than with others analogs
(Table 4), but additional data on larger and more
homogeneous series of patients must be collected before
definitive conclusions can be made. Comparative
randomized studies among the various formulations and
schedules of treatment are lacking but are highly advisable.
Further studies on larger series of boys with CPP are also
needed to better define the criteria for starting and
stopping the GnRH analog treatment to optimize the
outcome. In addition, the treatment is likely to be safe in terms of
testicular function, BMI and BMD in late adolescence, but
patients followed until young adulthood should be assessed
to draw definitive conclusions. Sonographic evaluation
of testicular texture, for example, at the discontinuation
of therapy and at final height, should be considered to
assess the presence of microcalcifications [19].
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