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Endocrine Care |
Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tiqva 49202, Israel; and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
Address all correspondence and requests for reprints to: M. Phillip, M.D., Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petah Tiqva 49202, Israel.
Abstract
The indication for GnRH analog treatment in boys with central sexual precocity is based mainly on the age of onset of puberty. Our aim was to determine whether the rate of pubertal progression should also be taken into consideration.
Included in the study were 81 boys with central sexual precocity: 27 with true precocious puberty (onset at <9 yr) and 54 with early puberty (onset at 9–10.5 yr). At the time of analysis, all had completed puberty, and 66 (22 central precocious puberty, 44 early puberty) had achieved final height. Progression of puberty (Tanner stage 2 to 3) was accelerated (0.5–1.32 yr) in 42 boys (16 central precocious puberty, 26 early puberty) and slow (1.7–2.9 yr) in 39 (11 central precocious puberty, 28 early puberty). The boys with accelerated puberty had significantly elevated T levels (central precocious puberty and early puberty, P < 0.001), faster growth rate (change in height SD score/duration: central precocious puberty, P < 0.05; early puberty, P < 0.01), and faster bone maturation rate (change in bone age/duration: central precocious puberty, P < 0.05; early puberty, P < 0.001). All 42 boys with accelerated puberty were treated with GnRH analog for 2.3–4.2 yr; the duration to completion of puberty and the height gain after therapy was discontinued were similar for the boys with central precocious puberty and early puberty. The 39 boys with slow puberty received no treatment and had a prolonged course of puberty (central precocious puberty, 5.05 ± 0.3 yr; early puberty, 4.72 ± 0.77 yr; average normal, 3.5 yr). The final height achieved in the 35 (11 central precocious puberty, 24 early puberty) untreated boys was within the range of their respective target height. The 31 (11 central precocious puberty, 20 early puberty) treated boys also achieved their genetic target height. Predictions based on the Bayley-Pinneau method at Tanner stage 3 for all boys and at discontinuation of therapy for treated boys overestimated the achieved final height (P < 0.001).
In conclusion, boys with sexual precocity, whether central precocious puberty or early puberty, may have either accelerated or slow pubertal development. The decision to institute suppressive therapy should be based also on the rate of pubertal progression. Treatment should be offered only to those (either central precocious puberty or early puberty) with accelerated growth and bone maturation rates and rapid increase in T levels. Suppression therapy apparently converts accelerated puberty into nonsustained slow puberty and probably prevents compromised final height.
IDIOPATHIC TRUE central precocious puberty (CPP) occurs significantly less often in boys than in girls (1, 2). Therefore, the majority of reports on CPP include only a relatively small number of boys (3, 4, 5, 6, 7, 8), and data on the course of puberty, indications for gonadotropin-suppressive therapy, and final height in this patient population are still sparse.
In boys with normal puberty, the first sign of sexual maturation (i.e. testicular enlargement, Tanner stage 2) appears at age 11.7 ± 1.3 yr; Tanner stage 3 is reached at age 13.2 ± 0.8 yr. The transition from Tanner stage 2 to 3 takes 1.5 yr, and the duration of the whole course of puberty is 3.5–4.0 yr (9, 10, 11). Precocious puberty in boys is defined as the appearance of pubertal signs before age 9 yr (1, 2). As precocious puberty may be complicated by significant psychosocial problems and may compromise final height (FHt), gonadotropin-suppressive therapy is recommended (1, 2, 3, 4, 5, 6, 7, 8, 12, 13).
Our experience has shown that in boys with true CPP, as in some affected girls, the rate of pubertal development is slow and attenuated, and puberty is completed close to normal age (14, 15, 16). By contrast, there are children in whom puberty appears early within the physiological age range and progresses at an accelerated rate, leading to a state of sexual precocity for age.
In this report we summarize our experience of the past 20 yr (1979–1999) with 81 boys with true CPP or early puberty (EP). Not only age at onset of puberty but also rate of pubertal progression were used as indications for gonadotropin- suppressive therapy. The objectives of the study were to evaluate the benefit of this treatment policy by the FHt achieved and to determine the accuracy of FHt prediction in boys with precocious puberty according to the tables of Bayley and Pinneau (17).
Subjects and Methods
Patients
Eighty-one boys with central sexual precocity were included in the study: 27 with true CPP (pubertal signs before age 9 yr; average age, 8.4 ± 0.41 yr) and 54 with EP (pubertal signs at age 9–10.5 yr; average age, 9.9 ± 0.52). The cut-off age of 10.5 yr for EP corresponds to the lower age of appearance of pubertal signs in normal boys (9, 10, 11). Excluded from the study were boys who were born prematurely or small for gestational age; boys with chronic disease, bone dysplasias, organic brain disease, or congenital adrenal hyperplasia; boys with other endocrine abnormalities; or boys who had received irradiation or chemotherapy. The clinical evaluation in all cases was performed by the same team, comprising pediatric endocrinologists, a radiologist, and nurses.
Diagnostic work-up
Height and weight were measured, and height SD score
was calculated in the patients and both parents according to the method
of Tanner and Whitehouse (18). The patients also underwent
complete physical examination and pubertal staging. Genitalia and pubic
hair development were determined according to Tanner, as was testicular
volume using the Prader orchidometer (Tanner 2, 4–6 ml; Tanner 3,
8–10 ml; Tanner 4, 12–15 ml; Tanner 5, 15–20 ml) (19).
Bone age (BA) was estimated according to the method of Greulich and
Pyle (20). Hormonal evaluation included basal plasma
levels of LH, FSH, T, dehydroepiandrosterone sulfate,
4-androstenedione, free
T4, TSH, 
-fetoprotein, and ßhCG. A
standard combined GnRH-ACTH stimulation test was performed to exclude
an adrenal enzymatic defect and to confirm that the sexual precocity
was of central origin. All hormonal examinations were performed by
standard techniques in the endocrine laboratory of our hospital, as
previously described (21, 22). The central nervous system
was imaged by computerized tomography or magnetic resonance technique
to exclude any abnormality of the brain. Psychological evaluation was
performed by a trained clinical psychologist.
Initial follow-up
When first seen in our institute, 65 of the 81 boys were at
Tanner stage 2 (21 CPP, 44 EP) and 16 were at Tanner stage 3 (6 CPP, 10
EP; Table 1
). The progression of the
pubertal course was analyzed after an initial follow-up of 2–6 months.
The course was considered accelerated if the transition from Tanner
stage 2 to 3 occurred within less than 1.5 yr and slow when it occurred
over more than 1.5 yr. Division of the 65 patients in Tanner stage 2 at
diagnosis by pace of pubertal course yielded 31 boys with accelerated
puberty (11 CPP, 20 EP) and 34 with slow puberty (10 CPP, 24 EP). Of
the 16 boys who were first seen at Tanner stage 3, physician
information was used to determine the pace of progression; 11 boys
showed an accelerated course (5 CPP, 6 EP), and 5 had a slow course (1
CPP, 4 EP). At Tanner stage 3, no significant differences for age,
height, bone maturation, or hormonal levels were found between the boys
initially seen at stage 2 and those seen at stage 3. Therefore, the 16
boys who presented at stage 3 were allocated to the respective
accelerated/slow progression groups together with the patients followed
from Tanner stage 2. The analysis of the data were based on all 81 boys
with sexual precocity, 42 with accelerated puberty (16 CPP, 26 EP), and
39 with slow puberty (11 CPP, 28 EP).
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Therapy was offered only to the boys with an accelerated course of puberty (both CPP and EP) who reached Tanner stage 3 before age 11.5 yr, i.e. 2 SD below the norm for that stage (13.2 ± 0.8 yr) (9, 10, 11). Treatment was started only after informed parental consent was obtained. There were no refusals.
Treatment consisted of an im injection of decapeptyl (depo-preparation
of D-Trp6-LHRH, Ferring Pharmaceuticals Ltd., Malmö, Sweden) administered
every 4 wk at a calculated dose range of 1.5–3.0 µg/kg released
(maximal dose per injection, 3.75 mg). Treatment was continued for
2.3–4.2 yr. Compliance was excellent, and there were no dropouts.
Therapy was stopped when chronological age (CA) was appropriate for
resumption of puberty (13–14 yr), BA was 13.5 yr or greater, and
growth velocity decreased to below the prepubertal rate (
4 cm/yr)
(20, 21).
Follow-up
All patients, treated and untreated, were followed regularly at 3- to 4-month intervals with height and weight measurements and clinical evaluation with pubertal staging. Bone age was determined every 6–12 months. Basal levels of LH, FSH, and T were measured in the treated boys 2–3 months after initiation of therapy to document suppression of secretion and in the untreated boys when the clinical evaluation revealed advance of puberty. All patients were followed until FHt was attained, i.e. when growth velocity dropped to less than 2 cm/yr, and BA was 17 yr or greater.
FHt
At the time of analysis, 66 of the 81 patients (22 of 27 CPP, 44 of 54 EP) had reached full puberty and completed their growth. The achieved FHt of the treated and the untreated boys was compared with their respective target height (THt), i.e. corrected midparental height, calculated according to Tanner et al. (23).
Predicted FHt
The predicted FHt was calculated according the method of Bayley and Pinneau (17). We used the tables for average boys because a previous study by our team in girls with sexual precocity had shown that the tables for average girls rendered more suitable FHt predictions than the tables for girls with accelerated puberty (24). The accuracy of the Bayley-Pinneau method was analyzed by comparing the achieved FHt to the predicted FHt at Tanner stage 3 for all boys and to the predicted FHt at discontinuation of GnRH analog (GnRH-A) therapy for the treated boys.
Statistical analysis
The data were analyzed with the BMDP program (25), and the results are expressed as the mean ± SD. Comparisons between groups and within groups of patients were performed with ANOVA or analysis of covariance with repeated measures, as appropriate.
Results
Clinical data at diagnosis (Table 1
)
At diagnosis, all of the boys with CPP (whether Tanner stage 2 or 3) were significantly taller (height SD score, P < 0.01) than the boys with EP, and their BA was more advanced for CA (BA/CA, P < 0.05).
Transition from Tanner stage 2 to 3
Of the 65 boys at Tanner stage 2 at diagnosis (21 CPP, 44
EP), 31 had an accelerated pubertal course (11 CPP, 20 EP), and 34 had
a slow course (10 CPP, 24 EP; Table 2).
For both CPP and EP, the growth rate (change in height SD
score/duration), the bone maturation rate (change in BA/duration), and
the rise in basal T levels during the transition from Tanner stage 2 to
3 were significantly greater in the accelerated puberty group than in
the slow puberty group. At Tanner stage 3, the basal and
GnRH-stimulated gonadotropin levels and the basal T levels (shown
in Table 3) were within
the pubertal range in all 81 patients (Table 3). T levels were
significantly higher in the accelerated puberty group (CPP,
P < 0.01; EP, P < 0.05), although
the plasma gonadotropin levels, both basal and GnRH stimulated, were
similar.
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)Treatment with GnRH-A was given at Tanner stage 3 to 42 boys with accelerated course of puberty [16 CPP (average age, 9.76 ± 1.07) and 26 EP (average age, 11.15 ± 0.36)]. At the time of institution of treatment, the boys with CPP were significantly taller (height SD score, P < 0.01) than the boys with EP, with a higher BA/CA ratio (P < 0.05). Although the bone maturation rate was increased during transition from Tanner stage 2 to 3 in the patients with an accelerated course, the BA/CA ratio was not markedly advanced in either CPP or EP patients.
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BA/duration). Treatment was
discontinued at age 13.44 ± 0.7 yr in boys with CPP and at age
14.1 ± 0.5 yr in boys with EP. The boys with CPP were still
taller than the boys with EP, but there was no significant difference
in BA. In all treated boys, resumption of puberty was noted (by clinical signs and hormonal levels) 4–6 months after discontinuation of therapy. Puberty was completed after similar periods of time in the boys with CPP and EP (1.65 ± 0.5 and 1.80 ± 0.46 yr, respectively). Height gain to FHt was also similar (9.3 ± 0.9 and 8.6 ± 1.3 cm, respectively).
Course in boys with slow puberty
The 39 of 81 boys (11 CPP, 28 EP) whose puberty progressed slowly were followed untreated. We found that their pubertal development from Tanner stage 3 to 5 was also relatively slow (CPP, 2.95 ± 0.43 yr; EP, 2.64 ± 0.43 yr), and the duration of puberty was long (CPP, 5.05 ± 0.3 yr; EP, 4.72 ± 0.77 yr) compared with the accepted average duration of normal puberty (3.5 yr) (9, 10, 11).
FHt
At the time of analysis, 66 of 81 boys had reached FHt, including
31 boys with accelerated puberty (11 CPP, 20 EP) and 35 with slowly
progressive puberty (11 CPP, 24 EP). The final height of the untreated
boys with slowly progressive sexual precocity was not significantly
different from their average respective THt (CPP, 172.06 ± 9.1
vs. 173.0 ± 7.8; EP, 167.7 ± 7.12 vs.
168.6 ± 5.6). The FHt of the GnRH-A-treated boys with accelerated
puberty was also not significantly different from their respective THt
(CPP, 172.25 ± 7.0 vs. 170.6 ± 4.46; EP,
166.3 ± 5.56 vs. 167.1 ± 4.5; Fig. 1). The FHt SDS of 25 of 31 treated boys
(81%; CPP, -9; EP, -16) and 26 of 35 untreated boys (74%; CPP,
-10; EP, -16) was ±1 SD score within their
genetic THt SD score, and the FHt
SD score of the remaining boys was within ±2
SD score of their THt range (Fig. 2).
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)For all 66 of 81 boys who had completed their growth at the time of analysis, regardless of the pubertal course, the predicted FHt at Tanner stage 3 was significantly overestimated compared with the achieved FHt (P < 0.001). Moreover, at discontinuation of GnRH-A therapy, the predicted FHt of the treated boys (CPP and EP) was even more exaggerated, as it was significantly improved compared with the prediction before therapy (P < 0.01).
Discussion
In the present study the decision to initiate suppressive therapy
for sexual precocity was based not only on the chronological age
(2, 3, 4, 5, 6, 7), but also on the rate of puberty. According to our
20-yr clinical experience, true CPP (onset of puberty before age 9 yr)
as well as EP (defined by us as pubertal onset at 9–10.5 yr) can have
either an accelerated or a slow attenuated course. Our study shows that
in the 39 of 81 boys with slowly developing sexual precocity (11 CPP,
28 EP), the transition from Tanner stage 2 to 3 and the duration of
puberty were longer than normal (9, 10, 11), and the clinical
signs were sustained, but progressed at a slow pace, without
significantly accelerated growth or bone maturation. Also, basal T
levels increased only moderately from Tanner stage 2 to 3. In view of
the attenuated progression of these parameters, there was no risk in
either CPP or EP patients of the undesirable consequences of sexual
precocity, namely, compromised adult height and psychosocial
embarrassment; therefore, gonadotropin-suppressive therapy was not
warranted. Similar data have been reported for girls with slowly
progressive sexual precocity (14, 15, 16). On the other hand,
in the boys with accelerated sexual precocity (CPP and EP), we observed
a fast progression of pubertal signs. The transition from Tanner stage
2 to 3 was shorter than normal (CPP, 1.08 ± 0.2 yr; EP, 0.9
± 0.4 yr; normal, 
1.5 yr), and Tanner stage 3 was reached at a
significantly younger age (CPP, 9.76 ± 1.07; EP, 11.15 ±
0.36 yr; normal, 13.2 ± 0.8 yr). Thus, the boys with accelerated
EP also achieved a state of sexual precocity for age. This course was
characterized by accelerated growth and bone maturation rates in both
the CPP and EP boys. Therefore, the use of GnRH-A therapy, which is not
controversial in boys with accelerated CPP (2, 3, 4, 5, 6, 7, 8), is, we
believe, also appropriate for boys with accelerated EP, especially
those with short stature in whom there is a risk of psychosocial
embarrassment and compromised adult height. It is noteworthy that the
boys referred to us with EP were significantly shorter not only than
the boys with CPP, but also than boys with normal puberty. This may
have been due to the selective frequent referral of short boys with EP,
who remain short despite their pubertal growth spurt for
endocrinological assessment, as opposed to the referral of all boys
with CPP regardless of their stature. This may be explained by the well
recognized association of compromised FHt with sexual precocity,
especially in a child with genetic short stature (1, 2, 3, 4, 5, 6, 7, 8).
It should be noted that as the boys with EP were selectively referred,
they may not serve as the best group for comparison, because their
heights are not representative of the general population.
The response to GnRH-A was similar in the EP and CPP boys, namely,
inhibition of pubertal progression and deceleration of growth and bone
maturation rate (Table 4), as was the resumption of puberty after
therapy. At discontinuation of therapy, although the boys with EP were
significantly older than the boys with CPP, their BAs were similar.
This explains the similar addition in height (8–10 cm) in the two
groups until FHt was achieved.
The benefit of therapy for sexual precocity is judged by the FHt achievement. All of our 31 GnRH-A-treated boys (11 CPP, 20 EP) who had completed growth by the time of this analysis achieved a FHt within the range of their respective THt. We presume that GnRH-A therapy benefited the patients by converting the accelerated pubertal process to one like that in the boys with slowly progressive puberty (EP and CPP), in whom final height is not compromised and THt is reached without treatment (14, 15, 16).
We offered therapy to all boys with accelerated sexual precocity, and we had no refusals from their families, presumably because the issue of height is more sensitive when boys are concerned. Therefore, as in other studies (3, 4), we have no control group of untreated boys, neither CPP nor EP, with an accelerated course. However, there have been reports on the FHt of GnRH-A-treated boys with CPP compared with untreated historic controls from the earlier literature, indicating that without therapy these boys can lose significant growth potential (up to 10 cm) (3, 26, 27, 28).
To the best of our knowledge, there are no reports on the FHt of boys with accelerated EP, untreated or treated with GnRH-A. According to the limited number of reports of girls with EP (pubertal signs appearing at age 8–10 yr), GnRH-A therapy has no effect on FHt. However, none of these studies considered the rate of pubertal development (13, 16, 29). A study of girls with EP conducted at our institute concluded that when the pubertal course is accelerated, FHt may be compromised, and this can presumably be prevented with GnRH-A therapy (30, 31).
We found that the Bayley-Pinneau method using the tables for average boys is not reliable for predicting FHt for boys with sexual precocity. The FHt predictions for our patients (CPP and EP), both treated and untreated, at Tanner stage 3 significantly overestimated the achieved FHt. This is in agreement with the findings of Oostdijk et al. (6), but not with other studies of GnRH-A-treated boys with CPP, in which the achieved FHt of treated boys was similar (4, 5) or even better (3) than the initially predicted FHt. However, there is a general agreement that GnRH-A therapy improves FHt predictions (3, 4, 5, 6, 8). This was noted here too. The predictions at discontinuation of therapy were even more exaggerated than those at its initiation (P < 0.01).
The greater reliability of the predictions by the Bayley-Pinneau method for girls with sexual precocity (3, 4, 5, 6, 20) may be attributable to their more advanced bone maturation in the early stages of precocious puberty (2, 3, 4, 5, 6, 7), perhaps because of the stronger stimulatory effect of the slight increase in estrogen level on the epiphyseal growth plate maturation (32, 33). In boys, the main stimulatory effect of androgens on bone maturation and growth (34) occurs later in puberty, toward Tanner stage 4 (1, 2, 31). Moreover, these androgens need to be aromatized to estrogens to advance bone maturation (35, 36, 37). Therefore, it may take longer for boys to generate sufficient estrogen during puberty to accelerate BA. This may be the explanation for the only moderate increase in the BA/CA ratio at Tanner stage 3. As the Bayley-Pinneau method of FHt prediction is based on BA, the less advanced BA in precocious boys at the early stages of puberty (Tanner stages 2–3) renders a better FHt prognosis, which is eventually not achieved.
Conclusion
In boys with true CPP as well as in boys with EP, the pubertal course can be accelerated or slowly progressive. The accelerated course is characterized by accelerated growth and bone maturation rates, a rapid transition from Tanner stage 2 to 3 (<1.5 yr) associated with T rise of more than 5 nmol/liter. Gonadotropin-suppressive therapy should be offered after a follow-up of at least 6 months only for boys with accelerated puberty, both CPP and EP (especially those with genetic short stature). When puberty progresses slowly, neither boys with CPP nor boys with EP need treatment.
The Bayley-Pinneau method is not reliable for FHt predictions in boys with sexual precocity and should not be used either when deciding on therapy or when evaluating its benefit.
Acknowledgments
We thank Dalia Peled and Clara Weininger of the nursing staff of the Department of Endocrinology, Pnina Lilus, for performing the statistical analysis, and Gloria Ginzach for her editorial assistance.
Footnotes
Abbreviations: BA, Bone age; CA, chronological age; CPP, central precocious puberty; EP, early puberty; GnRH-A, GnRH analog; THt, target height.
Received September 26, 2000.
Accepted May 17, 2001.
References
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L. de Vries, A. Kauschansky, M. Shohat, and M. Phillip Familial Central Precocious Puberty Suggests Autosomal Dominant Inheritance J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1794 - 1800. [Abstract] [Full Text] [PDF]
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