Eur J Pediatr (2008) 167:677681 DOI 10.

1007/s00431-007-0576-y

ORIGINAL PAPER

Adult height in children with short stature and idiopathic delayed puberty after different management
Stefano Zucchini & Malgorzata Wasniewska & Mariangela Cisternino & Mariacarolina Salerno & Lorenzo Iughetti & Mohamad Maghnie & Maria Elisabeth Street & Manuela Caruso-Nicoletti & Stefano Cianfarani

Received: 9 June 2007 / Accepted: 10 July 2007 / Published online: 24 August 2007 # Springer-Verlag 2007

Abstract By retrospectively collecting data from nine Italian centres of pediatric endocrinology, we assessed the different management and final outcome of children with short stature and idiopathic delayed puberty. Data were obtained in 77 patients (54 males, 23 females) diagnosed and followed-up in the various centres during the last 15 years. Inclusion criteria were short stature at initial observation and idiopathic delayed puberty diagnosed during follow-up. At first observation, age was 13.8 1.0 years and height standard deviation score (SDS) was 2.60.6 in males. In females age was 13.10.9 years and height SDS 2.60.4. Local diagnostic and therapeutic

protocols included testing for growth-hormone deficiency (six centres) and treatment in case of deficiency or, in the remaining centres, testosterone or no treatment in males, and no treatment in females. At diagnosis, both in males and in females, the auxological features (height SDS, target height SDS and bone age delay) were similar in the patients treated with growth hormone, testosterone or not treated. Overall 32 patients received growth hormone (25 males, 7 females), 33 no treatment (17 males, 16 females) and 12 testosterone. There was no difference in the adult height of males and females in the different treatment groups. In males there were no differences between adult and target

S. Zucchini (*) Department of Pediatrics, Azienda Ospedaliero-Universitaria di Bologna S. Orsola-Malpighi, via Massarenti 11, 40138 Bologna, Italy e-mail: zucchini@med.unibo.it M. Wasniewska Department of Pediatrics, University of Messina, Messina, Italy M. Cisternino Department of Pediatric Sciences, Instituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, University of Pavia, Pavia, Italy M. Salerno Department of Pediatrics, Federico II University of Napoli, Napoli, Italy L. Iughetti Department of Pediatrics, University of Modena and Reggio Emilia, Modena, Italy

M. Maghnie Department of Pediatrics, Instituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini, University of Genoa, Genova, Italy M. E. Street Department of Pediatrics, University of Parma, Parma, Italy M. Caruso-Nicoletti Department of Pediatics, University of Catania, Catania, Italy S. Cianfarani Department of Public Health and Cell Biology, Tor Vergata University, Roma, Italy

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height SDSs (growth hormone-treated 0.310.79, untreated 0.100.82, testosterone-treated 0.050.95), between adult and initial height SDSs (growth hormone-treated 1.70 0.93, untreated 1.550.92, testosterone-treated 1.531.43) and percentage of subjects with adult height above target height. In females, there were no differences between adult and target height SDSs (growth hormone-treated 0.491.13; untreated 0.100.97) and between adult and initial height SDSs (growth hormone-treated 1.760.92; untreated 1.77 0.98), whereas a significantly higher percentage of patients remained below target height in the growth hormone-treated group (6/7, 85.7% vs 5/11, 31.3%) (P =0.02). In conclusion, the diagnostic and therapeutic management of the patients with short stature and delayed puberty is different among Italian pediatric endocrinologists. Our data do not support the usefulness of growth-hormone therapy in improving adult height in subjects with short stature and delayed puberty, particularly in the female sex. Keywords Delayed puberty . Short stature . Adult height . GH therapy . Testosterone Abbreviations SDS standard deviation score GH growth hormone

the different centres and to verify whether the treatments prescribed were associated with a better statural outcome. Patients and methods We retrospectively collected data from 77 patients (54 males, 23 females) who were diagnosed and followed-up in nine Italian pediatric endocrinology university centres during the last 15 years. The patients had to meet both the following inclusion criteria: (1) stature below the 3rd centile and growth velocity <25th centile during the last 12 months (at first observation), and (2) idiopathic delayed puberty. The latter was retrospectively defined as follows: in males testicular volume <3.5 ml at age 13.5 years or <6 ml at age 14.5 years; in females lack of breast development M2 at age 12.5 years or M3 at age 13.5 years (Tanner score). The second parameter (in males testicular volume <6 ml at age 14.5 years and in females lack of breast development M3 at age 13.5 years) was introduced to also include subjects with a borderline value for age at puberty onset, but with a subsequent slow progression of pubertal development leading to a frankly delayed puberty. At first observation, in males, chronological age was 13.8 1.0 years and height standard deviation score (SDS) was 2.60.6; in females chronological age was 13.10.9 years and height SDS 2.60.4. Forty-two subjects and seven subjects respectively reported delayed puberty in one or both parents (as a whole, 63.6% of cases). Subjects with permanent hypogonadism and secondary causes of pubertal delay were not included in the study. Local protocols The various centres adopted different diagnostic and therapeutic protocols. In six centres, the patients were tested for GH deficiency, defined as peak GH <10 g/L after two different pharmacological stimuli from arginine, ldopa, clonidine, insulin and glucagon and treated with GH in case of deficiency. In the remaining three centres GH testing was not performed and the patients received either testosterone or no treatment. No centres primed the patients with sex steroids before the pharmacological tests. The choice between testosterone or no treatment in case of normal GH secretion or in the patients not tested was taken individually on the basis of gender (no treatment for female subjects) and on the evaluation of patient psychological disturbances owing to the growth delay (testosterone in case of major psychological suffering). GH dose range was 0.0200.035 mg kg1 day1 with seven injections per week. Therapy duration range was 2446 months. Depot testosterone (testosterone enanthate i.m.) dose ranged from 25 to 50 mg/month for a duration range of 312 months. Estrogen therapy was not used by any centre.

Introduction The diagnostic and therapeutic approaches of pediatric endocrinologists are often different when dealing with short stature associated with delayed puberty. Historically, therapeutic options include testosterone or oxandrolone in males, estrogens in females or no treatment if the clinician considers that height prediction is satisfactory and psychological repercussions are minor [2, 4, 79, 12, 17, 21, 23]. Growth-hormone (GH) treatment is an alternative option if GH secretion is studied and the child is found to be GH deficient [3]. Although most studies using androgens or no treatment report an adult height consistent with that of the parents, statural outcome is sometimes unfavourable, with a significant percentage of subjects ending up below the 3rd centile, as was recently confirmed [13]. We retrospectively collected the adult height data of patients examined for short stature and idiopathic delayed puberty from nine centres of pediatric endocrinology. All subjects had similar clinical characteristics at diagnosis and were differently managed and treated according to local protocols. We were able to compare the outcome of three groups of treatment: GH, testosterone or no treatment in males and no treatment vs GH treatment in females. Aims of our study were to compare the diagnostic management of

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The parameters considered for statistical analysis were height at diagnosis expressed as SDS, bone age delay, target height SDS, increase in adult height SDS defined both as the increase compared with height at diagnosis SDS and the difference from target height SDS. Height SDS was calculated with different parameters for children of northern-central Italy and children of southern Italy as appropriate [5, 6]. Adult height was defined when growth velocity fell below 1 cm in the last year of observation. Differences among groups were calculated using one-way ANOVA for multiple comparisons (Bonferroni test) in males and with Student t-test in females. The percentage of subjects with adult height above target height was analyzed using the chisquare test.

Discussion The present study shows the different management and final outcome of a patient series of Italian subjects affected by short stature and idiopathic delayed puberty. Our definition of delayed puberty could not be based on national data about the normal timing for puberty onset as such data are not available. However, the mean values we obtained for the appearance of Tanner G2 in males and for age at menarche in girls are in agreement with values for delayed puberty found in most industrialised countries [16]. Also the presence of a positive family history in about twothirds of our cases was helpful in confirming our diagnosis. The first result is that the management of children with short stature and delayed puberty is not uniform in Italian centres of pediatric endocrinology, both in terms of diagnostic approach and in type of therapy. Some centres in fact did not consider the simultaneous presence of pubertal delay in addition to short stature and simply performed GH testing. As for the possible therapy prescription in males, some centres tended to propose GH therapy in cases of deficiency, others tended to use testosterone in cases of normal GH secretion and yet others were probably more inclined, in male patients, not to perform any GH testing and simply to reassure the boy and the family that no treatment was necessary for what was considered a self-limiting problem. The therapeutic attitude in the different centres was more similar towards female patients, i.e., no centres used estrogens to correct the statural defect associated with pubertal delay. This was probably due both to a lesser demand from the girls to accelerate the pubertal progression and to uncertainties of the physicians as to the possible negative effects of estrogens on bone age. Furthermore, probably due to the lower prevalence of delayed puberty in females, little has been published about estrogen therapy in females, and also a published consensus guideline [9] was unable to define fixed criteria for treating pubertal delay in females. Estrogens in fact are mainly used to induce and

Results In males, mean chronological age at testicular volume 3.5 ml was 14.50.9 years. In females mean chronological age at breast development 2 was 14.10.7 years and mean age at menarche 15.91.5 years. In total, 42 subjects were tested for GH deficiency; 32 (25 males and 7 females) showed GH deficiency and were hence treated with GH. In the remaining 10 cases with normal GH secretion, the subjects received either no treatment (2 males, 3 females) or depot testosterone (5 males). As for the 35 subjects not tested for GH deficiency, 28 patients received no treatment (15 males, 13 females) and 7 testosterone (all males). The auxological features of the patients at diagnosis did not differ in the different groups of treatment and are reported in Table 1. At the end of follow-up, no significant differences among groups were detected (Table 2). In males, the percentage of subjects with adult height above target height was not different in the three groups, whereas in females a significantly higher percentage of subjects remained below target height in the GH-treated group (6/7, 85.7% vs 5/11, 31.3%) (P =0.02).

Table 1 Clinical characteristics at entry of the patients, subdivided into the three groups of treatment Males (n =54) Height SDS at diagnosis 2.620.55 Target height SDS 1.260.70 Bone age delay at diagnosis (years) 2.220.93 Females (n =23) Height SDS at diagnosis 2.680.30 Target height SDS 0.431.13 Bone age delay at diagnosis (years) 2.281.03

GH treated (n =25) Untreated (n =17) Testosterone treated (n =12)

2.570.65 2.830.72

1.120.77 1.450.53

2.090.92 2.471.0

GH treated (n =7) Untreated (n =16)

2.550.39

0.880.78

2.310.52

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Table 2 Clinical characteristics of patients at the end of growth subdivided into the three groups of treatment Males (n =54) Adult height (SDS) 0.920.76 Adult height target height SDS 0.310.79 Adult height initial height SDS 1.700.93 Females (n =23) Adult height (SDS) 0.920.80 Adult height target height SDS 0.491.13 Adult height initial height SDS 1.760.92

GH treated (n =25) Untreated (n =17) Testosterone treated (n =12)

1.020.75 1.390.87

0.100.82 0.050.95

1.550.82 1.531.43

GH treated (n =7) Untreated (n =16)

0.780.96

0.100.97

1.770.98

sustain puberty in subjects with permanent hypogonadism [20]. The centres participating in the study did not prime the patients with sex hormones before testing for GH. A probable interpretation of this homogeneous behaviour is that the centres more in favour of GH therapy did not agree with this diagnostic procedure, whereas those against the diagnosis of GH deficiency in this condition simply prescribed testosterone or no treatment. On the other hand, the subject continues to be debated [22], as does the usefulness of pharmacological tests in predicting response to treatment [10]. Concerning the adult height collected in nine Italian centres of pediatric endocrinology, we are obviously aware that our retrospective study was not randomly designed to identify the best treatment for improving adult height among GH, testosterone in males or no treatment in subjects with short stature and delayed puberty. However, to our knowledge, no such studies have been published so far. Despite the different diagnostic approaches of the various centres, we are convinced that the subjects examined were clinically quite similar, whether tested or not for GH deficiency and irrespective of the GH response to pharmacological tests. Since priming with sex steroids was not used in our patients, we cannot exclude that a significant percentage of our patients were falsely diagnosed as GH deficient [14] and maybe showed a blunted response to GH. However, in our opinion, our group of subjects showed similar clinical characteristics and if GH treatment had obtained a consistent height improvement, we would have been able to recognise it, despite the relatively small number of subjects. Our data, in fact, showed a similar statural outcome in the three treatment groups. First of all, in the male group, we confirm [2, 4, 9, 12, 17, 23] that testosterone therapy, useful for mitigating the psychological distress of the adolescent with delayed puberty, seems to lead to a similar adult height as the other groups. Second, GH treatment at the dose given, the most expensive and disturbing treatment in terms of daily

injections, seemed to produce no effects or even negative effects in our relatively small group of female patients. In fact, we found a higher percentage of female subjects with adult height below target height in the GH-treated group. On the other hand, the efficacy of GH therapy in the pubertal period except in cases of severe GH deficiency has not been demonstrated in either sex [18], and our data confirm the previous studies by Bierich et al. [3] and Adan et al. [1]. In comparison to what has been reported in the literature, a diagnosis of GH deficiency and subsequent replacement therapy were quite common (Table 1, 41% of cases) in the present case series, reflecting a probably unjustified expectation of the efficacy of GH treatment in this condition. Certainly the GH dose used in our patients mainly diagnosed in the 1990s was lower than that used successfully by Mauras et. al [15] in the pubertal period. Certainly new therapeutic options are needed to improve adult height in some of these patients, in particular for those at risk of becoming excessively short. Preliminary data showed that aromatase inhibitor letrozole has proved to be effective on near adult height in boys with constitutional delay of growth and puberty [11]. However, current limitations on height prediction in this kind of subject should always be considered [19].
Acknowledgements We are grateful to Professor Filippo De Luca for the critical revision of the manuscript.

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