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Endocrine Care |
Institute for Endocrinology and Diabetes, Schneider Children’s Medical Center of Israel, Petah Tiqva, 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
Early and fast puberty (EFP) in girls, defined as pubertal onset at age 8–9 yr, with an accelerated course, may cause compromised final height (FHt) and psychosocial distress. Treatment with a gonadotropin-suppressive agent is controversial, because the improvement in FHt is equivocal and there may be risk of obesity.
We analyzed the data of 126 girls with EFP: 63 treated with GnRH analog (GnRHA) since Tanner stage 3, for 2–4 yr; and 63 untreated. Age at onset of puberty; accelerated time of transition from Tanner stage 2 to 3 (<1.3 yr); and clinical, hormonal and sonographic findings were similar in the 2 groups. The girls given GnRHA treatment had a significantly prolonged pubertal course, compared with the accelerated course in the untreated girls (4.7 ± 0.4 vs. 2.45 ± 0.4 yr, P < 0.001). After therapy, they reached Tanner stages 4 and 5 and FHt at a significantly older age than the untreated group (P < 0.001), and their menarche was delayed (12.8 ± 0.6 vs. 10.8 ± 0.5 yr, P < 0.001). However, the different pace of puberty in the 2 groups did not change the total pubertal growth and the bone maturation rate. The Ht gain from Tanner stage 3 to 4 (10.4 ± 2.7 vs. 11.2 ± 3.1 cm) and from Tanner stage 4 to FHt (8.2 ± 2.7 vs. 8.8 ± 3.6 cm) was similar in the treated and untreated girls, as were absolute Ht and bone age at each pubertal stage. The weight gain of the treated girls was more pronounced during treatment (P = 0.0016), but it was arrested after discontinuation of therapy; and by the time FHt was reached, the body mass index was similar in the 2 groups.
The treated and untreated girls achieved a similar mean FHt, which was not significantly different from their respective mean target Ht (THt). Individual analysis revealed that 70% of the treated girls and 67% of the untreated girls attained their THt range (THt ± 0.5 SD) or surpassed it.
In conclusion, treatment with GnRHA affected only the pace of EFP. The similar Ht gain and bone maturation rate at each pubertal stage in the treated and untreated girls may suggest that the total pubertal growth is not dependent on pubertal duration and pace and is probably determined already at the onset of the normal pubertal development. The treatment did not compromise the FHt and did not cause long-lasting obesity. Therefore, GnRHA therapy may be suggested for use in girls who have psychosocial difficulties in coping with EFP.
IN GIRLS, ONSET of puberty at the lower physiological age range (i.e. 8–9 yr) is sometimes defined as being early but not precocious, and it is considered to be normal (1, 2). Early puberty may be accompanied by rapid pubertal development, with the girls reaching Tanner stage 3 before age 10 yr, which is significantly earlier than normal (11.9 ± 1.0 yr) (3). Combined early and fast puberty (EFP) leads to a state of so-called sexual precocity for age; and, like true central precocious puberty (CPP), it can cause psychosocial embarrassment (4, 5). Some authors believe it may also lead to compromised adult stature (6, 7). Therefore, these girls and their parents often seek medical advice. Suppressive therapy with GnRH analog (GnRHA) has been shown to arrest pubertal development in CPP and to decrease the accelerated growth and bone maturation to the prepubertal rate (5, 8, 9, 10). This therapy has also been offered to girls with EFP; but so far, its effects on final height (FHt) have been disappointing (6, 7). Moreover, some of the reports suggested possible side effects, such as excessive deceleration of growth rate, with subsequent worsening of the FHt prognosis (11, 12) and significant increase in body weight to frank obesity (10, 13, 14).
In a previous preliminary study of 67 girls with early puberty, we found that EFP can compromise FHt and that this outcome may be preventable with GnRHA therapy (15). In the present study, we report our expanded experience with 126 girls, all with sustained EFP, who were followed from 1980 to 2000; 63 were treated with GnRHA, and 63 were untreated. The aims of the study were to compare the 2 groups for course of EFP, growth pattern in each pubertal stage, FHt achieved compared with genetic target Ht (THt), and weight (Wt) changes.
Subjects and Methods
Patients
One hundred and twenty-six girls with EFP, attending the Endocrinology Clinic between 1980 and 2000, were studied. All met the following inclusion criteria: 1) appearance of first pubertal signs (breast buds and/or genital Tanner stage 2) (16), with or without sexual hair, between ages 8 and 9 yr; 2) fast transition [<1.3 yr (3)] from Tanner stage 2 to 3, accompanied by a recent acceleration of growth and bone maturation rate; 3) laboratory findings appropriate for midpuberty at age less than 9.5 yr: a) plasma LH response more than 7 mU/liter to GnRH stimulation and plasma estrogen levels appropriate for early puberty; and b) pubertal pelvic sonographic findings of increased uterine size and ovarian volume (17); and 4) regular follow-up to completion of puberty. Girls born prematurely or who were small for gestational age and girls with chronic diseases, bone dysplasias, organic brain diseases, congenital adrenal hyperplasia, or other endocrinological abnormalities were excluded, as were girls after radiation therapy and/or chemotherapy.
Treatment
Based on the therapeutic policy at that time, gonadotropin-suppressive therapy was offered to all the girls on the basis of a diagnosis of EFP, regardless of stature. Sixty-three accepted, with parental consent, and 63 refused. Those who refused were included in the study as controls. Therapy was started in those who consented at Tanner stage 3 and consisted of a depo-preparation of the superactive GnRH-analog D-Trp-6-LHRH (Decapeptyl, Ferring Pharmaceuticals Ltd., Malmö, Sweden), administered by im injection every 4 wk at a calculated dose of 1.5–3.0 µg/kg release per day (maximal dose per injection, 3.75 mg). Therapy was discontinued at chronological age (CA) 11–12 yr, bone age (BA) 12–12.5 yr, and/or growth velocity below 4 cm/yr. The duration of therapy was 2–4 yr.
Follow-up
All girls, treated and untreated, were regularly followed, at 4- to 6-month intervals, for Ht and Wt and pubertal stage. BA was determined every 6–12 months. All clinical and radiological evaluations were performed by the same team, comprised of pediatric endocrinologists, a radiologist, and nurses, until puberty was complete and FHt was attained, i.e. when BA was beyond 15 yr and growth velocity below 2 cm/yr. In the first years of the study, biochemical gonadal suppression during GnRH treatment was monitored by LHRH testing performed in 48 of 63 treated girls at 3–4 months after initiation of treatment, and by basal levels of LH and FSH at various intervals thereafter. In the latter years of the study, we validated hormonal suppression by measuring only basal levels of LH and FSH. In all the girls, LH and FSH were suppressed throughout the treatment period.
Methods
Ht was evaluated as Ht-SD score (Ht-SDS) and calculated for all girls and for both their parents, according to the method of Tanner and Whitehouse (18). Body weight was expressed as body mass index (BMI = Wt in kilograms/Ht in meters squared), and the BMI-SDS was calculated according to the method of Rosner et al. (19). Pubertal staging was determined according to Marshall and Tanner (16). BA was estimated according to Greulich and Pyle (20). Predicted final Ht (PFHt) was calculated by the method of Bayley and Pinneau (21) using the tables for average girls, which we have found to be more accurate in girls with sexual precocity (22). Target Ht (THt), i.e. the corrected midparental Ht, was calculated according to Tanner et al. (23). The THt range was defined as THt ± 0.5 SD. The hormonal evaluation included basal and GnRH-stimulated levels of LH and FSH and basal levels of E2. All hormonal examinations were performed by standard techniques, in the endocrine laboratory of our hospital, as previously reported (24). Abdominal and pelvic ultrasound examinations were performed by a trained radiologist using a Sonoline Prima (Siemens Medical Systems, Inc. Ultrasound Group, Issaquah, WA) 5 MHz device.
Statistical analysis
All analyses were done with the BMDP program (25), and the results are expressed as mean ± SD. Comparisons between and within groups were done with ANOVA and ANCOVA with repeated measures, as appropriate. Stepwise multiple logistic regression analysis was performed to determine the effects of some auxological variables on FHt.
Results
Findings for the relevant auxological parameters of the treated and untreated girls at Tanner stages 2 and 3 are presented in Table 1
. At Tanner stage 2, there were no significant differences between the groups for CA, BA, BA/CA ratio, Ht, Ht-SDS, Wt, BMI, or BMI-SDS. The transition from Tanner stage 2 to 3 was also similar in the treated and untreated girls but was significantly faster than in normal puberty (0.82 ± 0.26 and 1.01 ± 0.22 yr, respectively vs. 1.4 ± 0.12 yr for normal girls, P < 0.02) (3). It was accompanied by an accelerated growth rate (8.35 ± 2.45 and 7.97 ± 2.46 cm/yr, respectively), bone maturation rate (1.6 ± 0.24 and 1.48 ± 0.31 yr/yr, respectively), and Wt gain (
BMI, 0.95 ± 1.27 and 0.88 ± 1.15 kg/m2·yr, respectively). At Tanner stage 3, the treated group tended to be younger (P < 0.01), with a slightly more advanced BA than the untreated group (BA/CA ratio, P < 0.01); however, their BA, Ht, Ht-SDS, BMI, and BMI-SDS were still similar. The mean predicted FHt (PFHt) was also similar.
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Ht, 4.72 ± 0.95 cm/yr; BA, 0.57 ± 0.24 yr/yr), compared with the pretreatment rates. The Wt gain continued to be accelerated (BMI, 0.93 ± 0.73 kg/m2·yr). No side effects were observed or reported during the whole period of treatment. In all cases, puberty resumed several months after discontinuation of therapy, and menarche occurred within 1.67 ± 0.43 yr. In the untreated girls, the natural course of puberty continued to be fast. The transition from Tanner stage 3 to 4 lasted only 0.65 ± 0.24 yr (normal, 1.10 ± 0.15 yr) (3). Growth and bone maturation rates were accelerated (Ht, 8.15 ± 2.85 cm/yr; BA, 1.4 ± 0.55 yr/yr), as was the Wt gain (BMI, 0.83 ± 1.2 kg/m2·yr).
The whole duration of puberty in the treated girls was significantly longer than in the untreated girls (4.7 ± 0.4 vs. 2.45 ± 0.4 yr, P < 0.001), and their first menarche occurred at a significantly older age (12.8 ± 0.6 vs. 10.8 ± 0.5 yr, P < 0.001). Because of the significant age differences between the treated and untreated girls at Tanner stages 4 and 5 and FHt, we did not compare or analyze the auxological findings (Ht, Wt, and BMI) between the two groups in SDSs. The data at each stage are presented in centimeters, kilograms, and kilograms per meter squared, respectively. In spite of the significantly older age at which the treated girls reached Tanner stages 4 and 5 and FHt (P < 0.001), the BA and absolute Ht, in centimeters, of the treated and untreated girls were similar in relation to their pubertal stage (Table 2). There was no significant difference between the groups in mean Ht gain from Tanner stage 3 to 4 and from Tanner stage 4 to FHt (10.4 ± 2.7 vs. 11.2 ± 3.1 and 8.2 ± 2.7 vs. 8.8 ± 3.6 cm, respectively). The Wt gain of the treated girls was more pronounced (BMI, 2.0 ± 0.9 vs. 0.9 ± 0.1 kg/m2, P = 0.001), but it was arrested after therapy was discontinued (BMI, 1.1 ± 0.1 vs. 1.2 ± 0.3 kg/m2, P = NS). By Tanner stage 4, the Wt and BMI of the treated girls had increased significantly more than those of the untreated girls (for Wt, P < 0.002; for BMI, P = 0.0016); however, at Tanner stage 5, the differences in these parameters decreased (for Wt, P = 0.013; for BMI, P = 0.016), and the findings equalized when FHt was attained (Table 2).
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Discussion
The close and regular follow-up, from onset of puberty to FHt, of this large and quite homogeneous cohort of 126 girls with EFP enabled us to better understand the lack of effect (neither positive nor negative) of GnRHA therapy on FHt. Treatment starting at Tanner stage 3 attenuated puberty and delayed the transition from Tanner stage 3 to 4. Thus, the treated girls reached Tanner stage 4 and 5 and FHt, and had menarche, at a significantly later age than the untreated girls (P < 0.001). Nevertheless, the absolute Ht and BA at each pubertal stage were similar in the 2 groups (Table 2
, Fig. 1). Indeed, therapy caused a difference in growth rate between the 2 groups, but the absolute Ht gain was the same. The Ht gain, which was achieved by the untreated girls during a short period of time (because of their fast pubertal course), seemed to be accelerated; whereas in the treated girls, in whom it was achieved over a longer period (because of the GnRHA therapy), it seemed to be slow or even decelerated. Several authors have suggested that reduced GH secretion secondary to estrogen depletion may explain the growth deceleration during GnRHA therapy (11, 12, 26). However, the GH response to provocative stimuli during GnRHA treatment, tested in a previous study in several girls in our cohort (27), was found to be normal; this was true for other treated patients as well (28). Similarly, although the same BA was observed at each pubertal stage in both groups, there was a significant difference in the bone maturation rate. In the untreated girls, the increased bone maturation rate attributable to fast ossification of the cartilage (1, 2), in a significantly shorter time, resulted in a more advanced BA at a relatively younger CA, with a significant increase in BA/CA ratio. On the other hand, in the treated girls, GnRHA therapy, by suppressing estrogen secretion, attenuated and even arrested bone maturation for a prolonged period of time, resulting in a significant decrease in the BA/CA ratio. However, the arrest of bone maturation by GnRHA treatment was only temporary. Shortly after therapy was discontinued, there was a rapid advancement in bone maturation rate; and at Tanner stage 4, the BA of the treated girls was comparable with that of the untreated girls. This may be explained by a rapid increase in gonadotropins and estrogens, to late pubertal levels, because of activation by a mature hypothalamic GnRH-pulse generator that was not suppressed by the GnRHA therapy (29).
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). According to these findings, it seems that in physiologically normal (though early) puberty, the elongation potential of the growth plate at each pubertal stage is probably predetermined. Therefore, the bone growth for each pubertal stage is genetically inherent and is not affected by the pubertal pace. This is in contradistinction to accelerated true CPP (pubertal onset before age 7.5 yr), in which FHt is compromised unless the patient is treated with GnRHA (5, 8, 9, 22). A possible explanation for this difference is a probably more exaggerated response of the prepubertal growth plate to pubertal estrogen levels in CPP (31), resulting in a decreased bone-elongation potential.
Overweight and elevated BMI-SDS were observed in all our EFP girls from the early stages of puberty. GnRHA administered to only half the girls caused a significant Wt gain, compared with the untreated girls (P = 0.001). These findings differ from the reports on CPP girls, whose BMI-SDS were elevated throughout puberty, with no significant changes during or after GnRHA therapy (10, 13, 32). However, they are in agreement with the findings of Boot et al. (14), who related the accumulation of body fat over lean body mass to the estrogen depletion caused by the therapy. Palmert et al. (32) tried to explain these different findings on Wt gain of the GnRHA-treated girls, by the older age of some of the girls in the group with the pronounced Wt gain (i.e. girls with EFP). They suggested that girls with early puberty may respond differently, with regard to Wt gain to GnRHA treatment, than girls with CPP. The increased fat mass in treated girls has been regarded as a possible risk factor for permanent future obesity (10, 13, 32, 33). However, our data revealed that, after therapy was discontinued, the difference in BMI between the treated and untreated girls decreased; and by the time FHt was reached, the BMI had equalized (Table 2, Fig. 1). Hence, the gain in Wt caused by GnRHA is temporary and should not be a reason for sparing therapy.
The current equivocal data on the effect of gonadotropin-suppressive therapy on FHt may suggest that treating girls with EFP is not justified, especially in light of the current worldwide trend toward earlier pubertal development (34, 35). However, the emotional and social implications of sexual precocity for age, for many girls with EFP and their parents, cannot be disregarded (4). These girls may benefit from postponing their pubertal development until they reach an age of appropriate emotional maturity and can adjust more easily to sexual maturity.
In conclusion, pubertal growth potential and ultimate Ht in girls with EFP are probably predetermined very early in puberty and are not affected by pubertal pace, whether accelerated or attenuated by gonadotropin-suppressive therapy. Except for a temporary Wt gain, treatment with GnRHA had no adverse effects in the short run and is justified for girls with emotional difficulties caused by EFP.
Acknowledgments
We thank Dalia Peled, R.N., Clara Weininger, R.N., and Pnina Lilos for the statistical analysis; and Charlotte Sachs and Gloria Ginzach of the Editorial Board (Rabin Medical Center, Beilinson Campus) for assistance.
Footnotes
Abbreviations: BA, Bone age; BMI, body mass index; CA, chronological age; CPP, central precocious puberty; EFP, early and fast puberty; FHt, final height; GnRHA, GnRH analog; Ht, height; PFHt, predicted final height; SDS, SD score; THt, target Ht; Wt, weight.
Received October 3, 2001.
Accepted February 5, 2002.
References
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  J.-C. Carel, E. A. Eugster, A. Rogol, L. Ghizzoni, M. R. Palmert, and on behalf of the members of the ESPE-LWPES GnRH An Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children Pediatrics, April 1, 2009; 123(4): e752 - e762. [Abstract] [Full Text] [PDF]
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