Puberty and growth are very important physiological phenomena that entail vast changes.1 An increase in the secretion of gonadal steroid hormones triggers the onset of the pubertal growth spurt.2 It determines the growth velocity (GV) in puberty, sexual maturation and the age at menarche.3 Normal puberty starts from age 9 years with a testicular volume of 4 mL or greater measured with a Prader orchidometer in boys, and the development of breast buds in girls.4 Pubertal growth is important because it accounts for approximately 25% of total postnatal growth, slightly more in men.5 Abnormalities in pubertal growth are a frequent and clinically relevant reason for seeking medical care.1

Short stature is the most frequent presenting complaint in paediatric endocrinology practice.6 Short stature is defined as a height more than 2 standard deviations below the mean for age and sex in the reference population.7

Growth hormone deficiency (GHD) is an important cause of short stature in the paediatric population.8 It manifests differently depending on the stage of development when onset occurs (early after birth, during childhood, during adolescence or in adulthood), the underlying cause or mechanism (genetic, acquired or idiopathic), the severity and whether growth hormone (GH) is the sole affected pituitary hormone, other pituitary hormones are involved or the deficiency is part of a complex syndrome.9 There is ample evidence that early diagnosis and treatment of GHD are key due to its impact on neurodevelopmental, metabolic and anthropometric outcomes.8

The main goal of treatment with recombinant human growth hormone rhGH in these patients is to normalise linear growth during childhood and adolescence and achieve an adult height (AH) in the normal range and consistent with the genetic potential or target height (TH).10,11 Different clinical trials have demonstrated the efficacy of rhGH treatment for catch-up growth.7

Multiple studies suggest that initiation of treatment with rhGH at an early age increases the likelihood that patients will reach an AH consistent with the TH. Thus, treatment should start as early as possible to maximize the growth response.10,12 Other authors have proposed that the cumulative exposure to rhGH in prepubertal years is a significant factor and have found a correlation between linear growth in the prepubertal stage and total linear growth, which evinces the importance of initiating treatment before the onset of puberty.13,14

In this context, the objective of our study was to assess the response to treatment based on whether it was initiated before or after the onset of puberty, assess the potential correlation between initiation of treatment in the prepubertal stage and improved final height outcomes and, in patients that started treatment in the prepubertal stage, the possible benefits of early initiation of treatment.

The sample included 139 patients (96 female and 43 male). Of this total, 71.2% had severe GHD and 28.2% partial GHD. The mean concentration of GH in stimulation tests at diagnosis was 4.04 ± 2.57 ng/mL (0 ng/mL–9.86 ng/mL). The mean age at treatment initiation was 11.1 ± 2.5 years, with a mean duration of treatment of 4.2 ± 2 years, and a mean initial dose of 26.14 ± 2 µg/kg/day in the total sample, 26.02 ± 2.52 µg/kg/day in patients that started treatment before puberty and of 26.33 ± 2.14 µg/kg/day in patients that started it after the onset of puberty, without significant differences between the two groups (P = 0.454). The doses were similar during pubertal development. The mean age at the end of treatment was15.3 ± 1.2 years. The mean TH z-score was –1.3 ± 0.7, the mean initial height z-score –2.5 ± 0.4 and the mean initial PH z-score –2.19 ± 0.6, that is, 150.35 ± 3.40 cm for female patients and 164.9 ± 2.87 cm for male patients. The mean age at menarche was 13.67 ± 1 years.

Table 1 summarises birth data, parental heights and THs in the sample. Fig. 2 presents the results of the descriptive analysis of patient characteristics and outcomes during treatment. Table 2 compares height outcomes in patients that started treatment before and after the onset of puberty.

Figure 2.

Main characteristics of the patients and changes during the follow-up by sex.

(0.61MB).

A total of 61.9% patients started treatment with rhGH before the onset of puberty (40.3% of female patients and 21.6% of male patients), with a mean chronological age at treatment initiation of 9.87 ± 1.9 years in female patients and 10.14 ± 3.2 years in male patients. The mean time elapsed from initiation of rhGH to onset of puberty was 1 ± 2.2 years (1.4 ± 2.9 years in male patients and 0.8 ± 1.7 years in female patients). In the 38.1% of patients that started treatment after the onset of puberty, the mean age at initiation was 12.6 ± 0.9 years in female patients and 14.19 ± 1.4 years in male patients.

Patients reached AHs corresponding to z-scores that exceeded the baseline height z-scores relative to the reference population (AHz of –1.28 ± 0.6 vs initial height z of –2.5nbsp;± 0.4), with a mean AH of 154.5 ± 3.7 cm in female patients and 165.6 ± 4.1 cm in male patients. The difference between the AH and the TH z-scores was of 0.06 ± 0.7 and the difference between the AH and initial PH z-scores 0.9 ± 0.6. We found an increase of the AH relative to the initial height of 1.2 ± 0.6 standard deviations, corresponding to increases of +0.4 ± 0.5 in the prepubertal period and +0.84 ± 0.6 after the onset of puberty, without significant differences based on sex. The AH z-score was 0.57 ± 0.6 points greater compared to the PH at the onset of puberty. The total pubertal height gain (TPHG) was of 16.96 ± 3.9 cm in female patients and 25.04 ± 5.3 cm in male patients. Pubertal height gain was greater in patients that started treatment after the onset of puberty.

Linear growth after the onset of puberty was comparable to that in the reference population in male patients (25.04 ± 5.3 cm vs 26.2 ± 4.2 cm), with a tendency towards lesser growth (albeit not statistically significant) in patients that started treatment before puberty (24.24 ± 4.7 cm vs 26.2 ± 4.2 cm; P = 0.059). However, the height gain relative to the reference population was smaller in female patients (16.96 ± 3.9 cm vs 20.3 ± 4.4 cm), with statistically significant differences in the subset that started treatment before the onset of puberty relative to the reference population (16.74 ± 3.9 cm vs 20.3 ± 4.4 cm; P = 0.00) and to the group that started treatment after the onset of puberty (17.29 ± 3.9 cm vs 20.3 ± 4.4 cm; P = 0.00) (Table 3). We found a direct and significant correlation between TPHG and AH (r = 0.507; P = 0.00).

Both patients that started treatment in the prepubertal period (n = 86; AHz–THz = 0.14 ± 0.7) and those that started after puberty onset (n = 53; AHz–THz = –0.05 ± 0.7) reached their TH, with no significant differences between the groups (P = 0.126). Initiation of treatment in the prepuberal period was associated with better final outcomes (AH compared to initial height; P = 0.001) (Table 4). Furthermore, longer treatment in the prepubertal stage was significantly associated with better linear growth outcomes (Table 5).

Our study included 139 patients with GHD treated with rhGH for a minimum of 1 year that reached the near-final AH, which allowed us to analyse linear growth outcomes in a substantial number of patients. More than half the patients were female, a percentage similar to the proportions described in previous studies, including those published by Ranke et al.,20,21 Rachmiel et al.22 or Straetemans et al.23 but greater compared to other studies in which male patients predominated, such as the studies performed by Carrascosa et al.24,25 or Ariza Jiménez et al.26 This may be due to the size of the sample under study, and the sex distribution would probably be uniform if the sample were larger. However, the fact that we found a greater proportion of female patients highlights the importance of early diagnosis, as girls experience the onset of puberty earlier and reach the final height compared to boys, which has an impact on the potential total duration of treatment.

There is ample evidence of the positive impact of treatment with rhGH on GV,7,10,11 which was corroborated by our findings, as treatment with rhGH in our sample was effective in achieving AHs in the normal range consistent with the TH. Other aspects that are important in research on this subject are the assessment of adherence to treatment and the inclusion of other parameters to make a more comprehensive assessment.27

The age at onset of puberty in the male patients included in the sample was similar to the age reported in previous studies,3,19,28 except the study by Bundak et al.,29 in which boys experienced the onset of puberty earlier. In contrast, female patients in the sample experienced the onset of puberty at a later age compared to the previous literature,3,4,19 in which the age at onset of puberty is approximately 10 years, except for the study by Maghnie et al.28 in which the mean age was 12.6 years. The bone age at onset of puberty was consistent with the bone age reported in the studies by García-Cuartero et al.,4 Ferrández Longás et al.19 and Maghnie et al.28 The height and BMI of female patients in our study at onset of puberty were similar to those in the reviewed literature.3,4,28 Male patients in the sample had smaller heights compared to those reported by García Cuartero et al.,4 Maghnie et al28 and Bundak et al.,29 of around 147 cm, although the BMI values were similar. The mean age at menarche in our study was greater compared to the findings of longitudinal studies conducted by Carrascosa et al. (12.9 ± 1.1)3 and Ferrández Longás et al. (12.6 ± 0.9).19 The delay in the onset of puberty and menarche in female patients, which occurred later compared to longitudinal studies in healthy children, may be related to the pathophysiology of GHD, as the disease is characterised by proportionate decreased postnatal growth, including delayed puberty30 and delayed bone age31. However, although the age at onset of puberty and at menarche in female patients in the sample were greater compared to other case series, we ought to highlight that the time elapsed between the onset of puberty and menarche was consistent with the previous literature and with the reference population.3,19

Many studies suggest that initiation of treatment with rhGH at an early age helps patients achieve an AH in the range of their TH. Thus, treatment should be started as soon as possible to maximise linear growth outcomes.10,12 We found that 61.9% of patients had started treatment with rhGH before puberty at a chronological age at treatment initiation that was similar to those reported in studies like the one conducted by Ranke y Lindberg32 or the Kabi International Growth Study (KIGS)33 in both sexes. However, 38.1% started treatment after the onset of puberty, as the earliest patients included in the sample were treated long ago and started treatment when it was first authorised for management of GHD, and this percentage does not reflect current clinical practice, as diagnosis is made at younger ages, but the analysis of this subset is useful to compare responses to treatment based on the timing of initiation. In fact, we ought to highlight that we found a progressive decrease in the age at initiation of treatment from the earliest cases in the sample to the most recent ones.

In our study, the TPHG was similar to those reported by Maghnie et al.28 and Bundak et al.,29 but greater compared to the study by García-Cuartero et al.4 Based on our data, a higher TPHG is associated with greater AH outcomes, which supports the findings of other authors, including Ariza Jiménez et al.26 and Maghnie et al.28 A finding in our study that has not been described by previous authors was that the TPHG was greater in patients that started treatment in the pubertal period, which demonstrated the impact of puberty on final height. A possible explanation is that patients that started treatment in the prepubertal period had some catch-up growth before the onset of puberty, whereas those that started in the pubertal period had not yet started the catch-up growth and therefore had higher height gains during puberty.

The duration of treatment in the prepubertal period was considerably shorter compared to the duration reported by Carrascosa et al.3 in their longitudinal study, which was of 3.6 years. A possible explanation is that, as we mentioned before, some of the patients in our study were treated a long time ago.

Many studies have found an association between initiation of treatment before puberty onset and improved final height outcomes. The study conducted by Patel et al.13 found that younger age at treatment initiation and initiation in the prepubertal period were associated with better outcomes in patients with GHD. Consistent with the hypothesis that sensitivity to rhGH is greater during childhood and that treatment efforts to improve final height outcomes should focus on the prepubertal period, Root et al.12 found that catch-up growth in these patients took place during childhood, before the onset of puberty. The findings of Reiter et al.14 suggested that total exposure to rhGH in the prepubertal years could be a significant contributor to improved height outcomes, as the height gain in the prepubertal stage was strongly correlated to total height gain, thus confirming the importance of initiating treatment before puberty. Furthermore, in a study conducted more recently, Cavarzere et al.34 concluded that GH secretion should be re-evaluated mid-puberty to reduce potential adverse events and minimise costs without affecting final height outcomes. The effectiveness and cost-effectiveness of treatment with rhGH are therefore greater in the prepuberal period.10,32 Thus, as was also the case in our study, early initiation of treatment in the prepubertal period has been associated with better final height outcomes. However, our study included patients that started treatment in the prepubertal as well as pubertal periods, and found an association between the final height and initiation of treatment in the prepubertal period, assessed by the difference between the AH and the initial height. What our study contributes is that diagnosis of GHD in puberty should not limit treatment with rhGH, as the response to treatment was still adequate, although it is reasonable to assume that due to the shorter duration of treatment, the heigh gain will not be as great as if treatment had been initiated before the onset of puberty.

The study by Ranke et al.,20 to be interpreted taking into account the fact that the growth velocity decreases with age during the prepubertal period, found that in the group of patients that started treatment before the onset of puberty the response to rhGH was better in the youngest patients. Similarly, in the subset of patients with prepubertal initiation of treatment in our study, a longer duration of treatment before the onset of puberty was associated with better AH outcomes.

In conclusion, our findings reveal that patients that start treatment before the onset of puberty had better final height outcomes. In addition, the earlier treatment starts and the longer the duration of treatment in the prepubertal period, the better the outcome of treatment, although diagnosis of GHD after the onset of puberty does not preclude treatment with rhGH, as it can also achieve adequate outcomes. Furthermore, greater pubertal height gains lead to better final height outcomes. Our results corroborate the findings of previous studies and are relevant because they can guide clinical decision-making as regards the optimal timing for treatment initiation in order to maximise its benefits.

The authors have no conflicts of interest to declare.