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Horm Res 2003;60(suppl 1):68–73DOI: 10.1159/000071229 The KIGS Experience with the Addition of
Gonadotropin-Releasing Hormone Agonists to
Growth Hormone (GH) Treatment of Children
with Idiopathic GH Deficiency
Edward O. Reitera Anders Lindbergb Michael B. Rankec David A. Priced Kerstin Albertsson-Wiklande Christopher T. Cowellf Bert Bakkerb on behalf of the KIGS International Board aBaystate Medical Center Children’s Hospital, Tufts University School of Medicine Springfield, Mass., USA;bPharmacia Corporation, KIGS/KIMS Outcomes Research, Stockholm, Sweden; cPaediatric Endocrinology Section,University Children’s Hospital, Tübingen, Germany; dRoyal Manchester Children’s Hospital, Manchester, UK;ePediatric Growth Research Centre, University of Göteborg, Göteborg, Sweden; fInstitute of Endocrinology,Parramatta, Australia Key Words
ing hormone agonists (GnRHa) in order to see if a greater Growth hormone W KIGS W Children W Pubertal gain in height could be achieved by altering the tempo of maturation W Gonadotropin-releasing hormone pubertal maturation. Near-final height data were ana- agonists W Idiopathic growth hormone deficiency W lysed in 39 adolescents (out of a total of 249) who had received GH + GnRHa therapy and were compared withsimilar data from 1,893 patients with IGHD treated withGH alone. The total change in height SDS in boys who Abstract
received GH alone was +1.6, in contrast to +1.1 in GH + Although recombinant techniques have enabled the pro- GnRHa-treated boys; the total change in height SDS in duction of limitless amounts of human growth hormone girls who received GH alone was +1.4 in contrast to +1.1 (GH), and clinical methods for diagnosis and treatment in girls treated with GH + GnRHa. The near final height have been greatly enhanced, the mean final heights of SDS in girls treated with GH + GnRHa was 1.0 below the children with idiopathic GH deficiency (IGHD) treated mid-parental target height (MPH), whereas there was with GH remain in the range of –1.3 standard deviation only a –0.5 SDS difference in girls treated with GH.
scores (SDS) below normal height. One of the methods Approximation to the MPH did not differ in boys between used to increase height outcomes is to delay the onset the two treatment groups. These data suggest that the and progression of puberty to allow for a longer ‘pre- attainment of a substantial height SDS by manipulating pubertal’ growth phase. We reviewed the KIGS (Pharma- the tempo of puberty is limited, but that optimizing cia International Growth Database) data of patients with growth during the pre-pubertal phase is a more impor- IGHD who had been treated with gonadotropin-releas- Baystate Medical Center Children’s Hospital Tel. +1 413 794 5060, Fax +1 413 794 3623, E-Mail [email protected] Introduction
puberty; it is known, for example, that patients with GHDwith delayed puberty or hypogonadotropic hypogona- Patients with growth hormone deficiency (GHD) who dism achieve a taller height in adulthood [13, 17, 18].
receive treatment with biosynthetic growth hormone Precocious puberty can reduce the response to GH, (GH) have markedly improved actual or near-final height and so it may be an appropriate step to delay puberty with (NFH) outcomes, with an average final height approxi- a GnRH agonist (GnRHa) [19–21]. It is not yet clearly mating –1.3 standard deviations (SD) below the mean documented, however, whether the use of this strategy in reported in more than 1,400 patients from different regis- pubertal patients with GHD can enhance the final height tries and trials [1–11]. Yet despite the availability of mod- [22–28]. Small, controlled studies in adolescents with ern GH therapy, long-term studies still show that the GHD [26, 29] have shown that achievement of the MPH majority of patients fail to achieve their genetic target is possible when a GnRHa is added to the treatment regi- heights. Evaluation of final heights in 121 patients treated men. When these results were compared with data from in GH research trials conducted by Genentech indicated a the large NCGS database, however, the NCGS data did mean height standard deviation score (SDS) of –0.7, with not show greater gains with the use of GnRHa in a num- 106 patients being within 2.0 SDS of normal adult height ber of height growth parameters, other than a small gain in the USA [4]. Nevertheless, even in these patients, a in predicted final height before GH therapy in compari- –0.4 to –0.6 SDS difference from mid-parental target son with treatment with GH alone [30]. It seemed appro- height (MPH) still occurred. Achievement of the genetic priate, therefore, to review the KIGS data on patients target height is possible, as shown with a Swedish sub- with idiopathic GHD (IGHD) treated with GnRHa in group (from KIGS [Pharmacia International Growth Da- order to report the efficiency of a large multinational tabase]) of consistently treated patients who reached a median final height SDS of –0.32, which was equivalentto the MPH [11]. The data from this Swedish subgroup,however, are atypical.
As final height correlates with height at the onset of In total, 42,206 patients from 47 countries were entered in the puberty in patients with GHD [2, 12–15], every effort KIGS database as of August 2002, with 21,392 children of those hav- must be made to optimize growth velocity during pre- ing IGHD receiving therapy with GH alone (table 1). Out of these puberty and to achieve a height within the normal range 42,206 children, 249 were treated with a variety of regimens that at the onset of puberty. In data from two large internation- included GnRHa. The diagnosis of IGHD was made by the individu- al data registries (National Cooperative Growth Study al KIGS investigator according to the KIGS Aetiology ClassificationList and was based on a maximal level of GH of less than 10 ng/ml in [NCGS] and KIGS), the height gained during puberty in two standard GH stimulation tests. Neuroimaging had been per- patients with GHD was generally similar to that of formed in 45% of the patients and patients with structural abnormal- healthy children with delayed bone age [9, 16]. Pubertal ities in the hypothalamic-pituitary area were excluded.
height gain is negatively correlated with age at the onset of Table 1. Baseline characteristics of all boys
and girls with IGHD in KIGS: treatment
All values, except for the number of patients, are expressed as medians. Ht = Height; Table 2. Baseline characteristics of boys
and girls with IGHD who had achieved
near-final height: treatment with GH alone All values, except for the number of patients, are expressed as medians. Ht = Height; Table 3. Characteristics of boys and girls
with IGHD who had achieved near-final
height: at the start of puberty and the start All values, except for the number of patients, are expressed as medians. Ht = Height; Near-final height (NFH) was defined by a height velocity of less than 2 cm/year as calculated over a period of more than 9 months, achronological age of more than 16 years in boys and more than 14 Baseline characteristics of 1,893 GH-treated and 39 years in girls, or bone ages no less than 14 years in boys and 13 yearsin girls. GH therapy was at least 4 years in duration, with 1 year of GH + GnRHa-treated patients with IGHD, who had pre-pubertal treatment. MPH was calculated and expressed as an reached NFH are shown in table 2. In contrast to the 62% SDS, as described by Ranke et al. [16]. NFH was expressed in three prevalence of boys in the GH-treated group, only 41% of different ways, which are complementary to each other: (1) the actual children treated with GH + GnRHa were boys. The chil- height expressed as a height SDS; (2) the increment of height gained dren who required GnRHa therapy were older, with sig- (or change in height SDS), represented as NFH minus initial heightSDS; (3) the approximation to family target height, represented by nificantly more advanced skeletal maturation (p ! 0.01).
The groups were comparable in short stature and in height Data from 1,893 patients with IGHD treated with GH alone and deficits relative to family targets.
39 patients with IGHD treated with GH + GnRHa, all of whom had The characteristics describing the patients at the onset reached NFH, are described in this report (table 2). The details of the of puberty in the GH-treated group and at the start of regimens used by the investigators to suppress the hypothalamic-pituitary-gonadal axis and delay the onset and/or progression of GnRH therapy are shown in table 3. Approximately 90% puberty are not described in this report, as this information is not of the children in whom agonist treatment was initiated readily available from the database.
were in early puberty. There were no auxological differ-ences between the two patient groups except a change inheight SDS in which the GH + GnRHa groups had a sig-nificantly lower incremental gain (p ! 0.01).
Reiter/Lindberg/Ranke/Price/Albertsson-Wikland/Cowell/Bakker Fig. 1. Height SDS (Ht SDS) at the start of
GH therapy, at near-adult height (NAH)/
near-final height (NFH) and at NFH cor-
rected for mid-parental height (MPH) in (a)
boys and (b) girls with IGHD: treatment
with GH alone versus GH + GnRHa.
Table 4. Characteristics of boys and girls
with IGHD at near-final height
All values, except for the number of patients, are expressed as medians. Ht = Height; Characteristics of the patient groups at NFH are shown ing the pre-pubertal period and the relatively small contri- in table 4. The bone ages in the GH + GnRHa groups were bution of the height gained during puberty. These data lower than in the GH-treated groups, suggesting a poten- strongly suggest that manipulation of growth treatments tial for further growth. In male patients, the NFH closely during puberty might be less successful than aggressive approximated MPH in both groups, with the median dif- pre-pubertal management. Although recent data do not ferences being between –0.3 and –0.1 SDS (fig. 1a). In suggest that there is a long-term adverse effect on bone females, the NFH was not as close to MPH with a full mineralization by halting pubertal maturation with 1.0 SDS difference (F6 cm) in the GH + GnRHa group GnRHa [33, 34], it has been of concern [35]. Further- more, the delay of pubertal maturation in a child who isalready of short stature may have a detrimental psychoso-cial impact. These concerns and the limited successes Discussion
reported suggest that a cautious approach to the GH +GnRHa treatment regimen is merited.
Although the vast majority of experience with GnRHa In addition, in an effort to increase the final heights of in the treatment of children with gonadotropin-mediated patients with IGHD, the use of a high dose of GH during sexual precocity has shown a slowing in the tempo of puberty has been studied, based on the rationale that the puberty, delay in skeletal maturation, and improvement secretion of GH normally rises two- to fourfold during the in adult height over controls and pre-treatment predic- pubertal growth spurt with dramatic concomitant in- tions [31, 32], the addition of GnRHa to GH therapy regi- creases in serum levels of insulin-like growth factor I mens for patients with IGHD does not appear to have (IGF-I). It is also known that the pubertal growth spurt comparable value. Investigators conducting clinical stud- normally accounts for approximately 17% and 12% of ies of patients with GHD with delayed puberty or hypo- adult male and female height, respectively. In view of this, gonadotropic hypogonadism reported taller final heights Mauras et al. [36] evaluated substantially increased doses [13, 17, 18], suggesting that delaying pubertal progression of GH (0.1 vs 0.043 mg/kg/day) and found that the higher in patients with IGHD may be a reasonable strategy. Such dose only resulted in a 4.6 cm increase in NFH. The mean a treatment regimen in pubertal patients with GHD, how- height SDS achieved in the 0.043 mg/kg/day group (as in ever appealing it may seem, is not yet clearly documented the earlier report [4]) was –0.7 B 0.9, but 0.0 B 1.2 in the to enhance final height [22, 24, 25, 27, 28]. Although two 0.1 mg/kg/day group. This outcome was certainly similar small, controlled trials did demonstrate substantial effica- to the best data obtained with GnRHa, but concerns still cy, similar findings were not reported in data from the remain regarding the high levels of IGF-I attained during The data presented in this study of patients with Collectively, these findings suggest that puberty is not IGHD treated with either GH alone or GH + GnRHa in the optimal period to attempt to enhance the final height the KIGS database largely support the earlier findings outcome in patients with IGHD. Earlier diagnosis of from the NCGS [30], demonstrating an equivocal efficacy GHD with concomitant initiation of GH treatment, pro- for the addition of GnRHa to the GH treatment regimen.
gressive weight-related dose increments, strict attention Although children treated with GH + GnRHa were older to compliance with daily administration, and perhaps and had more advanced skeletal maturation at the start of titration of doses of GH based on frequent measurements the GH treatment than the GH-treated group, they were of IGF levels (or other GH-modulated peptides) may quite similar in height SDS and approximation to MPH at yield heights within the family target range.
the onset of puberty (GH-alone group) and the start ofGnRHa therapy (GH + GnRHa group). Growth duringpuberty in GH-treated boys was greater than in GH +GnRHa-treated boys, but the shorter MPH in the GH +GnRHa-treated boys allowed for a closer approximationto family height. In the girls, however, there were no bene-fits, and possibly even a deficit, from receiving GHalone.
Previous data in KIGS from patients with IGHD [16] have demonstrated the importance of height attained dur- Reiter/Lindberg/Ranke/Price/Albertsson-Wikland/Cowell/Bakker References
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