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Combined Use of Growth Hormone and Gonadotropin-Releasing Hormone Analogue in Short Normal Adolescent Girls: A Survey from Iran
GH and GnRH in short normal adolescent girls
COMBINED USE OF GROWTH HORMONE AND GONADOTROPIN-RELEASING HORMONE ANALOGUE IN SHORT NORMAL ADOLESCENT GIRLS: A SURVEY FROM IRAN Zohreh Karamizadeh, Mohammad Amin Kashef, Hamed Jalaeian, and Najmeh Namazee Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran.
Combined therapy with gonadotropin-releasing hormone (GnRH) analogue and growth hormone (GH) has been used to increase the height of adolescents who are not GH deficient and who have normally timed puberty. Its use, however, is still controversial. For 2 years simultaneously, we treated eight healthy girls with very low predicted adult height (PAH < 145 cm) who were entering into normally timed puberty. The GnRH analogue triptorelin pamoate (Decapeptyl, 100 +g/kg intramuscularly every 4 weeks) and GH (0.1 IU/kg/day subcutaneously, 6 days/week) were administered. The mean chronologic age (CA) of our patients was 11.01 ( 0.95 years, and mean bone age (BA) was 12.25 ( 1.13 years. With a height of 131.50 ( 5.83 cm (–2.37 ( 0.35 SD below the mean) and PAH of 140.87 ( 3.53 cm, they were all in Tanner stage 2–3 of puberty (except one patient in stage 4). In all cases, GH and thyroid hormone deficiency were ruled out before the study began. Height and BA were measured immediately after discontinuation of therapy. PAH was determined before and at the end of therapy. Combined treatment resulted in a 4.13 ( 1.19 cm increase in PAH (p < 0.01). Height increased significantly to 142.66 ( 3.54 cm at the end of treatment (p < 0.01). Height standard deviation score for CA increased from –2.37 ( 0.35 to –2.32 ( 0.67, showing no significant improvement (p = 0.5). Height age (HA)/BA ratio and BA/CA ratio both demonstrated significant growth during the treatment (p < 0.03 and p < 0.01, respectively), whereas HA/CA ratio did not improve significantly (p < 0.32). During treatment, puberty was completely suppressed in all cases. Combination therapy with GnRH analogue and GH resulted in significant improvement in height and PAH during therapy. Additional, and perhaps more long-term, studies are required to show whether this kind of treatment is effective in improving final adult height. The cost–benefit of such therapies should also be taken into account.
Key Words: short normal adolescents, growth hormone (GH), gonadotropin-releasing hormone (GnRH), height (Kaohsiung J Med Sci 2006;22:161–5)
Subjects with short stature and normal growth hormone (GH) secretion, termed “idiopathic short stature”, comprise
Received: August 12, 2005 Accepted: February 9, 2006 Address correspondence and reprint requests to: Dr. Zohreh Karamizadeh, Pediatrics Office, Namazee Hospital, Zand Avenue, 71937 Shiraz, Iran. E-mail: [email protected] Kaohsiung J Med Sci April 2006 • Vol 22 • No 4 © 2006 Elsevier. All rights reserved.
a very heterogeneous group of patients, including a large number of children with constitutional growth delay, familial short stature, or both. Clinicians have used a combination of GH and gonadotropin-releasing hormone (GnRH) analogue in children with idiopathic short stature [1]. Increased secretion of GH plays an important role in the pubertal growth spurt. The effect of GH on final height can 161
Z. Karamizadeh, M.A. Kashef, H.Jalaeian, et al
be influenced negatively by the rapid bone maturation that is seen in puberty [2]. On the other hand, GnRH analogues slow bone-age (BA) progression and rapid growth, and have the potential to extend the time available for pubertal growth [3]. Therefore, there is increasing interest in the role of postponing puberty as a component of growth-promoting therapy. Many research groups have investigated the effects of various doses and lengths of treatment on adult height. For instance, in cases of idiopathic short stature, GH alone has been used with controversial results [4–6]. GnRH analogues alone also have been used in the same condition, still with controversial results [7,8]. We evaluated the effect of combined therapy with GH and GnRH analogue on eight girls with idiopathic short stature and normally timed puberty.
PATIENTS AND METHODS Eight short girls with a mean chronologic age (CA) of 11.02 ( 0.95 years and a mean BA of 12.25 ( 1.13 years were studied. All were comparatively short in stature, with a mean height of 131.50 ( 5.83 cm (–2.37 ( 0.35 SD below the mean) and mean predicted adult height (PAH) of 140.87 ( 3.53 cm. All were in early puberty: Tanner stage 2–3 for breasts and pubic hair (except one subject in Tanner stage 4). All girls were healthy and well nourished without any identifiable endocrine, chromosomal or systemic illness; or any history of perinatal insult, intrauterine growth retardation; or other possible causal medical conditions.
The clinical characteristics of our subjects are depicted in Table 1. GH deficiency was ruled out by a normal GH response to administration of L -DOPA and propranolol on two separate occasions. Complete blood cell count, routine blood chemistries, and thyroid function tests were also normal in all subjects before the beginning of treatment. This study was approved by our university ethics committee. Informed consent was obtained from the subjects and their parents after discussing both the auxologic and endocrine findings on each child, as well as explaining the probable effects of treatment. Subjects received GH at a dose of 0.1 IU/kg/day given subcutaneously for 6 days per week (Novo Nordisk A/S, Bagsværd, Denmark) and the GnRH analogue triptorelin pamoate (Decapeptyl, Beaufour Ipsen, Paris, France) at a dose of 100 +g/kg, administered intramuscularly, every 4 weeks. Both medications were started simultaneously, and all patients were treated for 24 months. Height was measured with a stadiometer by the same examiner, and the mean of three measurements was recorded at the beginning, at 3-month intervals, and at the termination of therapy. BAs were measured before and after the treatment by the same radiologist using the method of Greulich and Pyle [9]. PAHs were calculated by the method of Bayley and Pinneau [10]. Routine chemistries and complete blood cell counts were obtained at each 4-month visit. Data are expressed as the mean ( SD unless otherwise stated. Because the number of cases was limited, statistical analysis was performed using nonparametric tests (Wilcoxon matched-pairs signed-ranks test).
Table 1. Clinical characteristics of patients at entry into the study Patient no.
1 2 3 4 5 6 7 8 Mean ( SD
CA (yr)
10.17 10 11 10.5 10.25 11.75 12 12.5 11.02 ( 0.95
BA (yr)
11 11.5 12 11 12 13 13.5 14 12.25 ( 1.13
Height (cm)
124 126 130 128 130 136 138 140 131.50 ( 5.83
Pubertal status (Tanner) Breast
Pubic hair
3 3 3 3 3 3 3 4 –
2 3 3 3 3 3 3 4 –
PAH (cm)
132.5 143.7 141 143 141 141 142 142.75 140.87 ( 3.53
BA = bone age; CA = chronologic age; PAH = predicted adult height.
162
Kaohsiung J Med Sci April 2006 • Vol 22 • No 4
GH and GnRH in short normal adolescent girls
RESULTS
Height after treatment was 142.66 ( 3.54 cm; this value was 1.79 ( 2.21 cm greater than the PAH before the start of treatment (140.87 ( 3.52 cm) (p < 0.05) (Figure) and was below the PAH after treatment (145.66 ( 2.34 cm).
Combined treatment with the GnRH analogue and GH resulted in an interruption of pubertal development in all patients. Height increased significantly from 131.50 ( 5.83 cm at the beginning to 142.66 ( 3.54 cm at the end of treatment (p < 0.01). BA and PAH increased from 12.25 ( 1.13 years to 13.97 ( 1.00 years and from 140.87 ( 3.53 cm to 145.66 ( 2.34 cm, respectively; the latter was statistically significant (p < 0.01). Auxologic data of the patients are given in Table 2. Whereas height age (HA)/BA ratio and BA/CA ratio both increased significantly during treatment (p < 0.03 and p < 0.01, respectively), HA/CA ratio did not change significantly. HA was 9.19 ( 1.05 years at the beginning of treatment and reached 11.19 ( 0.62 (Table 3). Height, expressed as SD score for CA (Ht SDS-CA), increased from –2.37 ( 0.35 to –2.32 ( 0.67 at the end of treatment, but showing no prominent growth (p = 0.57) (Table 3).
DISCUSSION GH therapy is now used for treating short stature in subjects not deficient in GH, but the administration of this therapy is controversial. One reason is that short subjects who are not deficient in GH are a heterogeneous group, including patients with different clinical and hormonal characteristics. The effect of long-term GH treatment on short children not deficient in GH has been reported by some researchers. Hintz et al treated 121 short children, who were not deficient in GH, with GH for 2–10 years [4]. In 80 children, adult height was increased to a level above the PAH and above the adult height of untreated historical control children This agrees with the reports by Finkelstein et al [5] and Leschek et al [6].
Table 2. Auxologic data of patients before and after therapy
BA (yr) Height (cm) PAH (cm) Ht SDS-CA HA/BA ratio HA/CA ratio BA/CA ratio
Before treatment
After treatment
12.25 131.50 140.87 –2.37 0.74 0.83 1.12
13.97 142.66 145.66 –2.32 0.80 0.86 1.07
( ( ( ( ( ( (
1.13 5.83 3.53 0.35 0.02 0.04 0.03
( ( ( ( ( ( (
Statistical significance
1.00 3.54 2.34 0.67 0.05 0.05 0.03
Insignificant p < 0.01* p < 0.01* Insignificant p < 0.03* Insignificant p < 0.01*
BA = bone age; CA = chronologic age; HA = height age; PAH = predicted adult height. *Values are the mean ( SD. p < 0.05 was considered significant.
Table 3. Chronologic age, height age, and SD score for chronologic age of patients before and after therapy Patient no. 1 2 3 4 5 6 7 8 Mean ( SD
Chronologic age
Height age
SD score for CA
Before treatment
After treatment
Before treatment
After treatment
Before treatment
After treatment
10.17 10 11 10.5 10.25 11.75 12 12.5 11.02 ( 0.95
12.17 12 13 12.5 12.5 13.75 14 14.5 13.05 ( 0.93
7.75 8.25 9 8.5 9 10 10.25 10.75 9.19 ( 1.05
9.75 11.25 11.25 11.25 11.25 11.75 11.25 11.75 11.19 ( 0.62
–3.02 –2.31 –2.37 –2.61 –1.90 –2.39 –1.97 –2.41 –2.37 ( 0.35
–2.97 –1.33 –2.26 –2.05 –1.51 –2.45 –3.26 –2.71 –2.32 ( 0.67
CA = chronologic age.
Kaohsiung J Med Sci April 2006 • Vol 22 • No 4
163
Height (cm)
Z. Karamizadeh, M.A. Kashef, H.Jalaeian, et al 148 147 146 145 144 143 142 141 140 139 138 137 PAH before treatment
Height after treatment
Figure. Predicted adult height (PAH) before and height after treatment (p < 0.05).
On the other hand, Hindmarsh and Brook suggested that the small increment in final height does not justify the widespread use of GH for short normal children [11]. In order to delay or slow pubertal development, the addition of GnRH analogues to GH therapy in peripubertal subjects, who are not deficient in GH, is justified. GnRH analogues are widely used for treating central precocious puberty. These agents suppress gonadotropins and gonadal steroid secretions, resulting in the slowing of bone maturation [1,2,12]. For idiopathic short stature, combined treatment of GnRH analogues and GH has been performed, leading to conflicting results for adult height. Municchi et al found in their study that the pubertal delay induced by long-term use of GnRH analogues increased the predicted adult height of adolescence with short stature and normally timed puberty [8]; the same result was achieved by Kamp et al [13]. Saggese et al also found combined therapy to be useful in increasing the height prognosis of subjects without GH deficiency and normal-onset puberty [14], but in another study conducted by Balducci et al, despite the significant improvement in predicted height during treatment, this form of therapy did not result in an increase in adult stature [12]. Lanes and Gunczler also reported that the final height of patients did not improve significantly compared with PAH before treatment [15]. In this study, eight short-stature normal girls with PAH of less than 145 cm were treated with GnRH analogue and GH. GH was administered in daily doses of 0.1 IU/kg 6 days per week; this is equal to the amount used in some other studies [12,15]. We used Decapeptyl (100 +g/kg intramuscularly every 4 weeks) instead of Leuprolide, which was used in higher doses by others [12,15]. In the present study, low doses of GnRH analogue were adequate to 164
suppress pubertal development in all patients; because the patients were in the early stages of puberty, higher doses would have been redundant. Combined treatment resulted in a significant increase in PAH, similar to the findings of Saggese et al [14], with comparable duration of treatment, number of patients, and pubertal status. Ht-SDS-CA did not show a prominent rise, similar to findings of Saggese et al [14], and Lanes and Gunczler [15]. Height after treatment was significantly greater than PAH before treatment; Pasquino et al also came to the same conclusion while treating patients for a longer period and with higher doses [16]. In the present study, we did not measure final adult height. At discontinuation of therapy, in some patients, the growth plates were still not completely calcified, so height at this stage was not final adult height. BA/CA, HA/ BA, and HA/CA ratios are three predictors of final adult height. HA/BA ratio improved significantly after treatment (p < 0.03). The same result was achieved by Balducci et al [12] and Saggese et al [14]. BA/CA decreased at the end of treatment, similarly to another study [14], implying the effectiveness of combined treatment on delaying bone maturation. To summarize, combined treatment of eight normal girls with idiopathic short stature and normally timed puberty, using GH and GnRH analogue for 2 years, resulted in suppression of puberty, delay of bone maturation, and increase in height and PAH. Possible disadvantages of postponing puberty using GnRH analogue include weight gain and psychosocial consequences, such as withdrawn behavior, anxiety, depression, and social problems [2]. In the present study, weight gain was the only side effect noted in all treated patients. Considering the economic and ethical costs, these therapies should be limited and individualized to very short subjects in whom a gain of even a few centimeters could be considered worthwhile. Additional long-term investigations are required to evaluate the precise effect of combined treatment on final adult height in individuals with idiopathic short stature.
REFERENCES 1. Kaplowitz PB. If gonadotropin-releasing hormone plus growth hormone (GH) really improves growth outcomes in short non-GH-deficient children, then what? [Editorial] J Clin Endocrinol Metab 2001;86:2965–8. Kaohsiung J Med Sci April 2006 • Vol 22 • No 4
GH and GnRH in short normal adolescent girls 2. Wit JM, Visser-Van Balen H, Kamp GA, et al. Benefits of postponing normal puberty for improving final height. Eur J Endocrinol 2004;151:S41–5. 3. Kohn B, Julius JR, Blethen SL. Combined use of growth hormone and gonadotropin-releasing hormone analogues: the national cooperative growth study experience. Pediatrics 1999;104:1014–8. 4. Hintz RL, Attie KM, Baptosta J, et al. for the Genentech Collaborative Group. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502–7. 5. Finkelstein BS, Imperiale TF, Speroff T, et al. Effect of growth hormone therapy on height in children with idiopathic short stature. Arch Pediatr Adolesc Med 2002;156:230–40. 6. Leschek EW, Rose SR, Yanovski JA, et al. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89: 3140–8. 7. Cutler GB, Yanovski JA, Rose SR. Luteinizing hormonereleasing hormone against (LHRHa)–induced delay of epiphyseal fusion increases adult height of adolescents with short stature. Horm Res 1997;48(Suppl 2):28. 8. Municchi G, Rose SR, Pescovitz OH, et al. Effect of deslorelininduced pubertal delay on the growth of adolescents with short stature and normally timed puberty: preliminary results. J Clin Endocrinol Metab 1993;77:1334–9.
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9. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd edition. Stanford: Stanford University Press, 1969. 10. Bayley N, Pinneau S. Tables for predicting adult height from skeletal age: revised for use with Greulich-Pyle standards. J Pediatr 1952;40:423–41. 11. Hindmarsh PC, Brook CG. Final height of short normal children treated with growth hormone. Lancet 1996;348:13–6. 12. Balducci R, Toscano V, Mangiantini A, et al. Adult height in short normal adolescent girls treated with gonadotropinreleasing analogue and growth hormone. J Clin Endocrinol Metab 1995;80:3596–600. 13. Kamp GA, Mul D, Waelkens JJJ. A randomized controlled trial of three years growth hormone and GnRH agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001;86:2969–75. 14. Saggese G, Cesaretti G, Barsanti S, et al. Combination treatment with growth hormone and gonadotropin-releasing hormone analogues in short normal girls. J Pediatrics 1995;126,468–73. 15. Lanes R, Gunczler P. Final height after combined growth hormone and gonadotropin releasing hormone analogue in short healthy children entering into normally timed puberty. Clin Endocrinol 1998;49:197–202. 16. Pasquino AM, Pucarelli I, Roggini M, et al. Adult height in short normal girls treated with gonadotropin-releasing hormone analogues and growth hormone. J Clin Endocrinol Metab 2000;85:619–22.
165
COMBINED USE OF GROWTH HORMONE AND GONADOTROPIN-RELEASING HORMONE ANALOGUE IN SHORT NORMAL ADOLESCENT GIRLS: A SURVEY FROM IRAN Zohreh Karamizadeh, Mohammad Amin Kashef, Hamed Jalaeian, and Najmeh Namazee Department of Pediatrics, Shiraz University of Medical Sciences, Shiraz, Iran.
Combined therapy with gonadotropin-releasing hormone (GnRH) analogue and growth hormone (GH) has been used to increase the height of adolescents who are not GH deficient and who have normally timed puberty. Its use, however, is still controversial. For 2 years simultaneously, we treated eight healthy girls with very low predicted adult height (PAH < 145 cm) who were entering into normally timed puberty. The GnRH analogue triptorelin pamoate (Decapeptyl, 100 +g/kg intramuscularly every 4 weeks) and GH (0.1 IU/kg/day subcutaneously, 6 days/week) were administered. The mean chronologic age (CA) of our patients was 11.01 ( 0.95 years, and mean bone age (BA) was 12.25 ( 1.13 years. With a height of 131.50 ( 5.83 cm (–2.37 ( 0.35 SD below the mean) and PAH of 140.87 ( 3.53 cm, they were all in Tanner stage 2–3 of puberty (except one patient in stage 4). In all cases, GH and thyroid hormone deficiency were ruled out before the study began. Height and BA were measured immediately after discontinuation of therapy. PAH was determined before and at the end of therapy. Combined treatment resulted in a 4.13 ( 1.19 cm increase in PAH (p < 0.01). Height increased significantly to 142.66 ( 3.54 cm at the end of treatment (p < 0.01). Height standard deviation score for CA increased from –2.37 ( 0.35 to –2.32 ( 0.67, showing no significant improvement (p = 0.5). Height age (HA)/BA ratio and BA/CA ratio both demonstrated significant growth during the treatment (p < 0.03 and p < 0.01, respectively), whereas HA/CA ratio did not improve significantly (p < 0.32). During treatment, puberty was completely suppressed in all cases. Combination therapy with GnRH analogue and GH resulted in significant improvement in height and PAH during therapy. Additional, and perhaps more long-term, studies are required to show whether this kind of treatment is effective in improving final adult height. The cost–benefit of such therapies should also be taken into account.
Key Words: short normal adolescents, growth hormone (GH), gonadotropin-releasing hormone (GnRH), height (Kaohsiung J Med Sci 2006;22:161–5)
Subjects with short stature and normal growth hormone (GH) secretion, termed “idiopathic short stature”, comprise
Received: August 12, 2005 Accepted: February 9, 2006 Address correspondence and reprint requests to: Dr. Zohreh Karamizadeh, Pediatrics Office, Namazee Hospital, Zand Avenue, 71937 Shiraz, Iran. E-mail: [email protected] Kaohsiung J Med Sci April 2006 • Vol 22 • No 4 © 2006 Elsevier. All rights reserved.
a very heterogeneous group of patients, including a large number of children with constitutional growth delay, familial short stature, or both. Clinicians have used a combination of GH and gonadotropin-releasing hormone (GnRH) analogue in children with idiopathic short stature [1]. Increased secretion of GH plays an important role in the pubertal growth spurt. The effect of GH on final height can 161
Z. Karamizadeh, M.A. Kashef, H.Jalaeian, et al
be influenced negatively by the rapid bone maturation that is seen in puberty [2]. On the other hand, GnRH analogues slow bone-age (BA) progression and rapid growth, and have the potential to extend the time available for pubertal growth [3]. Therefore, there is increasing interest in the role of postponing puberty as a component of growth-promoting therapy. Many research groups have investigated the effects of various doses and lengths of treatment on adult height. For instance, in cases of idiopathic short stature, GH alone has been used with controversial results [4–6]. GnRH analogues alone also have been used in the same condition, still with controversial results [7,8]. We evaluated the effect of combined therapy with GH and GnRH analogue on eight girls with idiopathic short stature and normally timed puberty.
PATIENTS AND METHODS Eight short girls with a mean chronologic age (CA) of 11.02 ( 0.95 years and a mean BA of 12.25 ( 1.13 years were studied. All were comparatively short in stature, with a mean height of 131.50 ( 5.83 cm (–2.37 ( 0.35 SD below the mean) and mean predicted adult height (PAH) of 140.87 ( 3.53 cm. All were in early puberty: Tanner stage 2–3 for breasts and pubic hair (except one subject in Tanner stage 4). All girls were healthy and well nourished without any identifiable endocrine, chromosomal or systemic illness; or any history of perinatal insult, intrauterine growth retardation; or other possible causal medical conditions.
The clinical characteristics of our subjects are depicted in Table 1. GH deficiency was ruled out by a normal GH response to administration of L -DOPA and propranolol on two separate occasions. Complete blood cell count, routine blood chemistries, and thyroid function tests were also normal in all subjects before the beginning of treatment. This study was approved by our university ethics committee. Informed consent was obtained from the subjects and their parents after discussing both the auxologic and endocrine findings on each child, as well as explaining the probable effects of treatment. Subjects received GH at a dose of 0.1 IU/kg/day given subcutaneously for 6 days per week (Novo Nordisk A/S, Bagsværd, Denmark) and the GnRH analogue triptorelin pamoate (Decapeptyl, Beaufour Ipsen, Paris, France) at a dose of 100 +g/kg, administered intramuscularly, every 4 weeks. Both medications were started simultaneously, and all patients were treated for 24 months. Height was measured with a stadiometer by the same examiner, and the mean of three measurements was recorded at the beginning, at 3-month intervals, and at the termination of therapy. BAs were measured before and after the treatment by the same radiologist using the method of Greulich and Pyle [9]. PAHs were calculated by the method of Bayley and Pinneau [10]. Routine chemistries and complete blood cell counts were obtained at each 4-month visit. Data are expressed as the mean ( SD unless otherwise stated. Because the number of cases was limited, statistical analysis was performed using nonparametric tests (Wilcoxon matched-pairs signed-ranks test).
Table 1. Clinical characteristics of patients at entry into the study Patient no.
1 2 3 4 5 6 7 8 Mean ( SD
CA (yr)
10.17 10 11 10.5 10.25 11.75 12 12.5 11.02 ( 0.95
BA (yr)
11 11.5 12 11 12 13 13.5 14 12.25 ( 1.13
Height (cm)
124 126 130 128 130 136 138 140 131.50 ( 5.83
Pubertal status (Tanner) Breast
Pubic hair
3 3 3 3 3 3 3 4 –
2 3 3 3 3 3 3 4 –
PAH (cm)
132.5 143.7 141 143 141 141 142 142.75 140.87 ( 3.53
BA = bone age; CA = chronologic age; PAH = predicted adult height.
162
Kaohsiung J Med Sci April 2006 • Vol 22 • No 4
GH and GnRH in short normal adolescent girls
RESULTS
Height after treatment was 142.66 ( 3.54 cm; this value was 1.79 ( 2.21 cm greater than the PAH before the start of treatment (140.87 ( 3.52 cm) (p < 0.05) (Figure) and was below the PAH after treatment (145.66 ( 2.34 cm).
Combined treatment with the GnRH analogue and GH resulted in an interruption of pubertal development in all patients. Height increased significantly from 131.50 ( 5.83 cm at the beginning to 142.66 ( 3.54 cm at the end of treatment (p < 0.01). BA and PAH increased from 12.25 ( 1.13 years to 13.97 ( 1.00 years and from 140.87 ( 3.53 cm to 145.66 ( 2.34 cm, respectively; the latter was statistically significant (p < 0.01). Auxologic data of the patients are given in Table 2. Whereas height age (HA)/BA ratio and BA/CA ratio both increased significantly during treatment (p < 0.03 and p < 0.01, respectively), HA/CA ratio did not change significantly. HA was 9.19 ( 1.05 years at the beginning of treatment and reached 11.19 ( 0.62 (Table 3). Height, expressed as SD score for CA (Ht SDS-CA), increased from –2.37 ( 0.35 to –2.32 ( 0.67 at the end of treatment, but showing no prominent growth (p = 0.57) (Table 3).
DISCUSSION GH therapy is now used for treating short stature in subjects not deficient in GH, but the administration of this therapy is controversial. One reason is that short subjects who are not deficient in GH are a heterogeneous group, including patients with different clinical and hormonal characteristics. The effect of long-term GH treatment on short children not deficient in GH has been reported by some researchers. Hintz et al treated 121 short children, who were not deficient in GH, with GH for 2–10 years [4]. In 80 children, adult height was increased to a level above the PAH and above the adult height of untreated historical control children This agrees with the reports by Finkelstein et al [5] and Leschek et al [6].
Table 2. Auxologic data of patients before and after therapy
BA (yr) Height (cm) PAH (cm) Ht SDS-CA HA/BA ratio HA/CA ratio BA/CA ratio
Before treatment
After treatment
12.25 131.50 140.87 –2.37 0.74 0.83 1.12
13.97 142.66 145.66 –2.32 0.80 0.86 1.07
( ( ( ( ( ( (
1.13 5.83 3.53 0.35 0.02 0.04 0.03
( ( ( ( ( ( (
Statistical significance
1.00 3.54 2.34 0.67 0.05 0.05 0.03
Insignificant p < 0.01* p < 0.01* Insignificant p < 0.03* Insignificant p < 0.01*
BA = bone age; CA = chronologic age; HA = height age; PAH = predicted adult height. *Values are the mean ( SD. p < 0.05 was considered significant.
Table 3. Chronologic age, height age, and SD score for chronologic age of patients before and after therapy Patient no. 1 2 3 4 5 6 7 8 Mean ( SD
Chronologic age
Height age
SD score for CA
Before treatment
After treatment
Before treatment
After treatment
Before treatment
After treatment
10.17 10 11 10.5 10.25 11.75 12 12.5 11.02 ( 0.95
12.17 12 13 12.5 12.5 13.75 14 14.5 13.05 ( 0.93
7.75 8.25 9 8.5 9 10 10.25 10.75 9.19 ( 1.05
9.75 11.25 11.25 11.25 11.25 11.75 11.25 11.75 11.19 ( 0.62
–3.02 –2.31 –2.37 –2.61 –1.90 –2.39 –1.97 –2.41 –2.37 ( 0.35
–2.97 –1.33 –2.26 –2.05 –1.51 –2.45 –3.26 –2.71 –2.32 ( 0.67
CA = chronologic age.
Kaohsiung J Med Sci April 2006 • Vol 22 • No 4
163
Height (cm)
Z. Karamizadeh, M.A. Kashef, H.Jalaeian, et al 148 147 146 145 144 143 142 141 140 139 138 137 PAH before treatment
Height after treatment
Figure. Predicted adult height (PAH) before and height after treatment (p < 0.05).
On the other hand, Hindmarsh and Brook suggested that the small increment in final height does not justify the widespread use of GH for short normal children [11]. In order to delay or slow pubertal development, the addition of GnRH analogues to GH therapy in peripubertal subjects, who are not deficient in GH, is justified. GnRH analogues are widely used for treating central precocious puberty. These agents suppress gonadotropins and gonadal steroid secretions, resulting in the slowing of bone maturation [1,2,12]. For idiopathic short stature, combined treatment of GnRH analogues and GH has been performed, leading to conflicting results for adult height. Municchi et al found in their study that the pubertal delay induced by long-term use of GnRH analogues increased the predicted adult height of adolescence with short stature and normally timed puberty [8]; the same result was achieved by Kamp et al [13]. Saggese et al also found combined therapy to be useful in increasing the height prognosis of subjects without GH deficiency and normal-onset puberty [14], but in another study conducted by Balducci et al, despite the significant improvement in predicted height during treatment, this form of therapy did not result in an increase in adult stature [12]. Lanes and Gunczler also reported that the final height of patients did not improve significantly compared with PAH before treatment [15]. In this study, eight short-stature normal girls with PAH of less than 145 cm were treated with GnRH analogue and GH. GH was administered in daily doses of 0.1 IU/kg 6 days per week; this is equal to the amount used in some other studies [12,15]. We used Decapeptyl (100 +g/kg intramuscularly every 4 weeks) instead of Leuprolide, which was used in higher doses by others [12,15]. In the present study, low doses of GnRH analogue were adequate to 164
suppress pubertal development in all patients; because the patients were in the early stages of puberty, higher doses would have been redundant. Combined treatment resulted in a significant increase in PAH, similar to the findings of Saggese et al [14], with comparable duration of treatment, number of patients, and pubertal status. Ht-SDS-CA did not show a prominent rise, similar to findings of Saggese et al [14], and Lanes and Gunczler [15]. Height after treatment was significantly greater than PAH before treatment; Pasquino et al also came to the same conclusion while treating patients for a longer period and with higher doses [16]. In the present study, we did not measure final adult height. At discontinuation of therapy, in some patients, the growth plates were still not completely calcified, so height at this stage was not final adult height. BA/CA, HA/ BA, and HA/CA ratios are three predictors of final adult height. HA/BA ratio improved significantly after treatment (p < 0.03). The same result was achieved by Balducci et al [12] and Saggese et al [14]. BA/CA decreased at the end of treatment, similarly to another study [14], implying the effectiveness of combined treatment on delaying bone maturation. To summarize, combined treatment of eight normal girls with idiopathic short stature and normally timed puberty, using GH and GnRH analogue for 2 years, resulted in suppression of puberty, delay of bone maturation, and increase in height and PAH. Possible disadvantages of postponing puberty using GnRH analogue include weight gain and psychosocial consequences, such as withdrawn behavior, anxiety, depression, and social problems [2]. In the present study, weight gain was the only side effect noted in all treated patients. Considering the economic and ethical costs, these therapies should be limited and individualized to very short subjects in whom a gain of even a few centimeters could be considered worthwhile. Additional long-term investigations are required to evaluate the precise effect of combined treatment on final adult height in individuals with idiopathic short stature.
REFERENCES 1. Kaplowitz PB. If gonadotropin-releasing hormone plus growth hormone (GH) really improves growth outcomes in short non-GH-deficient children, then what? [Editorial] J Clin Endocrinol Metab 2001;86:2965–8. Kaohsiung J Med Sci April 2006 • Vol 22 • No 4
GH and GnRH in short normal adolescent girls 2. Wit JM, Visser-Van Balen H, Kamp GA, et al. Benefits of postponing normal puberty for improving final height. Eur J Endocrinol 2004;151:S41–5. 3. Kohn B, Julius JR, Blethen SL. Combined use of growth hormone and gonadotropin-releasing hormone analogues: the national cooperative growth study experience. Pediatrics 1999;104:1014–8. 4. Hintz RL, Attie KM, Baptosta J, et al. for the Genentech Collaborative Group. Effect of growth hormone treatment on adult height of children with idiopathic short stature. N Engl J Med 1999;340:502–7. 5. Finkelstein BS, Imperiale TF, Speroff T, et al. Effect of growth hormone therapy on height in children with idiopathic short stature. Arch Pediatr Adolesc Med 2002;156:230–40. 6. Leschek EW, Rose SR, Yanovski JA, et al. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89: 3140–8. 7. Cutler GB, Yanovski JA, Rose SR. Luteinizing hormonereleasing hormone against (LHRHa)–induced delay of epiphyseal fusion increases adult height of adolescents with short stature. Horm Res 1997;48(Suppl 2):28. 8. Municchi G, Rose SR, Pescovitz OH, et al. Effect of deslorelininduced pubertal delay on the growth of adolescents with short stature and normally timed puberty: preliminary results. J Clin Endocrinol Metab 1993;77:1334–9.
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9. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd edition. Stanford: Stanford University Press, 1969. 10. Bayley N, Pinneau S. Tables for predicting adult height from skeletal age: revised for use with Greulich-Pyle standards. J Pediatr 1952;40:423–41. 11. Hindmarsh PC, Brook CG. Final height of short normal children treated with growth hormone. Lancet 1996;348:13–6. 12. Balducci R, Toscano V, Mangiantini A, et al. Adult height in short normal adolescent girls treated with gonadotropinreleasing analogue and growth hormone. J Clin Endocrinol Metab 1995;80:3596–600. 13. Kamp GA, Mul D, Waelkens JJJ. A randomized controlled trial of three years growth hormone and GnRH agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001;86:2969–75. 14. Saggese G, Cesaretti G, Barsanti S, et al. Combination treatment with growth hormone and gonadotropin-releasing hormone analogues in short normal girls. J Pediatrics 1995;126,468–73. 15. Lanes R, Gunczler P. Final height after combined growth hormone and gonadotropin releasing hormone analogue in short healthy children entering into normally timed puberty. Clin Endocrinol 1998;49:197–202. 16. Pasquino AM, Pucarelli I, Roggini M, et al. Adult height in short normal girls treated with gonadotropin-releasing hormone analogues and growth hormone. J Clin Endocrinol Metab 2000;85:619–22.
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