Final Height and Pubertal Development in 150 Children with Growth Hormone Deficiency in Algeria  

Fedala S.N.1 , Chentli F.2 , Meskine D.2 , Haddam A.E.M.2
1.Department of endocrinology bab el oued hospital, Algeria
2.Department of endocrinology bologhine hospital, Algeria
Author    Correspondence author
International Journal of Clinical Case Reports, 2015, Vol. 5, No. 45   doi: 10.5376/ijccr.2015.05.0045
Received: 16 Jun., 2015    Accepted: 25 Aug., 2015    Published: 10 Nov., 2015
© 2015 BioPublisher Publishing Platform
This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Preferred citation for this article:

Fedala S.N., Chentli F., Meskine D.,and Haddam A.E.M., 2015, Final Height and Pubertal Development in 150 Children with Growth Hormone Deficiency in Algeria, International Journal of Clinical Case Reports, 5(45) 1-6 (doi: 10.5376/ijccr.2015.05.0045)

Abstract

Growth Hormone Deficiency (GHD) may happen when the body is unable to produce enough growth hormone (GH) or use it effectively. GH plays a fundamental role in helping young bodies grow and develop puberty. When levels of GH are too low, there may be an impact on growth and many functions of the body.We report in this study, the results on the final height and pubertal development of 150 Algerian patients followed in our department of endocrinology.

The average age at diagnosis was 8 ± 2.4 in girls and 9 ± 1.2 in boys. The GH deficiency was isolated in half of the cases, associated with other hypophyseal deficits in the other half; hormonal deficiencies were all substituted. Patients received irregular treatment with GHr the average height of patients GHD at diagnosis in boys: -4,7DS ± 1,8) /(Sempé) and -4,1DS 0,8/ TC; In girls -4,9DS ± 2,3(- 11,8, - 2,8)/(Sempé) and -5, 2 1,2/TC.

Average final height: -3,4 1,02/ Sempé; - 2,1 1,1/TC in boys and - 3,8 1,06/ Sempé and - 3,8 1,03/TC in girls. The average age at onset of puberty in girls: 13.9 2.8 years. At the end of puberty: 17.4 2.8 years. The age of menarche: 15.52 years. In boys, the average At the end of puberty: 19.8 2.2 years. The average duration of the course of puberty is 3.7 0.7 years in boys, 3.1 1,1 years in girls. Delayed puberty is higher in boys than in girls (p <0.04).
 

Keywords
GH deficiency; GHr; Final height; Puberty

Introduction
Growth Hormone Deficiency may happen when the body is unable to produce enough growth hormone (GH) or use it effectively. GH plays a fundamental role in helping young bodies grow and develop, including improving muscle metabolism, growing bones, and breaking down fats.When levels of GH are too low, there may be an impact on growth and many functions of the body (Job, 1983) (Carroll and Christ) (Barat, 1999) (G.H. Research society, 2000).

Objective: To determine final height and puberty in children with GH deficiency (GHD) who have completed puberty.

Population, Methodology
This is about a prospective, longitudinal analytical study of 150 GHD patients whose diagnosis was based on a set of clinical and para-clinical arguments (G.H research society, 2000): Anamnestic and clinical characteristics GH deficiency, Radiological assessments (AO), Non-hormonal biological assessments of orientation, the low rate of IGF1 and the negative answer to both pharmacological tests of GH stimulation. The average age at diagnosis was 8 ± 2.4 (7-19) in girls and 9 ± 1.2 (8-18) in boys. The GH deficiency was isolated in half of the cases (51%), associated with other hypophyseal deficits in the other half (49%): gonadotropic 28%, TSH + ACTH: 18.63% - ACTH1: 4.01% - TSHus: 13.08% - diabetes insipidus: 3.73%. Hormonal deficiencies were substituted. Patients received irregular treatment with recombinant growth hormone (GHr) due to frequent breakdown of the product during the follow-up period or lack of resources because the treatment was not paid in any case.

The treatment was stopped when the growth rate was residual (less than 2 cm/year) with an age greater than 15 years.

Patients underwent a clinical analysis of anthropometric parameters (height and weight) to diagnosis, early and during puberty and late growth.

A monitoring puberty also was performed in all patients; it was reported the age at puberty, their progression and age of menarche in girls.

A Careful analysis of the importance of height and weight deficit was performed for each patient by comparing the weight and height to the referential values for the age on the Sempé and Pedron curves (expressed in standard deviation (SD) according to the reference tables expressed in standard deviations score (SDS) (Perelman and Perelman, 1994; Sempe, 1979) and in relation to parental target height calculated using the formula) (Perelman and Perelman, 1994) and in relation to parental target height (TC): TC = father height (cm) + mother height (cm) 13 depending to the sex 2NB: + 13 in boys and - 13 in girls.

Secondary sexual characteristics and course of puberty were evaluated from the classification of Tanner and Marshall (1976).

The results were analyzed with computer software Epi Info Version 6.4 after recording data on individual entry form. The methods used were: -The calculation of arithmetic averages (X ± SD). The comparison between two averages is based on student test and the reduced difference.

-Arithmetic percentages calculation (p%). The comparison between two percentages is based on the chi 2 test and the reduced difference. The significance rate was p <0.05.

Results:
The growth retardation is severe in GH patients whether expressed in DS or SDS with no significant difference between the sexes (DNS).

The calculation of the average growth rate of patients during the year prior to treatment initiation by GHr shows that the growth rate  is significantly reduced compared with the theoretical growth rate: 2.6±0.4 cm/year vs. 5 cm / year (P <10-6).71.7% of patients had a spontaneous pubertal development. The average age at onset of puberty in girls is 13.9 years  2.8 years (11.5 to 18).

The average age at the end of puberty in girls is 17.4 2.8 years (15-23). The age at the end of puberty in girls is more delayed than that given by Marshall (p <0.005).

The age of menarche in girls was 15.5  2 years (14-20).This average age is significantly delayed compared with the theoretical age given by Marshall p <005.

The average course of puberty in girls was 3.1  1,1 years (2.2 to 5). This is comparable to the theoretical average course of puberty.

The age of menarche in those girls was 15.5  2 years (14-20).This average age is significantly delayed compared with the theoretical age given by Marshall p <005.

The average course of puberty in girls was 3.1  1,1 years (2.2 to 5). is comparable to the theoretical average course of puberty.

In boys: the average age of onset of puberty is 16.4  2.4 years (12.4 to 19). This age is delayed compared
The average age at the end of puberty is 19.8  2.2 years (16-23). This average age is later than that given by Marshall (p<0.000 5).

The average duration of the course of puberty is normal of 3.7  0.7 years (3 -6).

Delayed puberty is higher in boys than in girls (p <0.04).

The final height of GH patients who completed their puberty is very low among both boys and girls with no significant difference between them.

Discussion
The causes of short height are numerous and their respective frequency differs slightly depending on whether it relates to paediatrics or endocrinology (Vimpani et al., 1977; Job and Pierson, 1981; Bao et al., 1992; Bessona et al., 2003)

Although the growth hormone deficiency is not involved in a little less than 10% of growth delays, its recognition is important because it leads to a specific treatment that improves stature prognosis (Job and Pierson, 1981).

The exact prevalence of this disorder is unknown in Algeria. In Europe and the United States, it is variously estimated and varies between 1/4000 and 1/10 000 (August et al., 1990).

When the diagnosis is suspected, it is advisable carry out a quick and paraclinical exploration and to undertake substitutive treatment with biosynthetic growth hormone in order to correct the stature deficit because in the absence of substitutive hormone, the spontaneous evolution is a dwarfism with adult final height between - 4 and -7 DS / TC (Job, 1992; Besson et al., 2003).

The main effect of growth hormone treatment is to stimulate during childhood growth in stature and thus enable obtaining adult height that is equal to the target height. In addition to this very important effect, growth hormone plays a key role in body composition, carbohydrate and lipid metabolism and bone mass (Albertsson-wikland, 1999; Abdu, 2001).

A significant improvement in the final height with biosynthetic growth hormone was found in the literature. This is correlated in addition to parental height, early diagnosis, optimization of treatment and height at onset of puberty. Bernasconi et al. (2000), Blethen et al. (1993) and Cutfield et al. (1999) have clearly demonstrated through their large series the correlation existing between age at start of treatment and the final height.

The bad results regarding the final height of our patients are explained by the late age at diagnosis and getting started hormone substitutive therapy. The irregular, inadequate and the non repayment of the treatment that our country knew before the last decade explain the stature evolution of GH D. These results are almost those of a spontaneous evolution. The ignorance of the disease and abnormalities of growth by many practitioners and the lack of systematic monitoring of all children by the growth curve explain the long delay in diagnosis and the start up treatment. Yet the growth curve reflects the health of the child and any slowdown or break of the growth rate should lead to undertake an informed etiological exploration.

In terms of sexual development, pubertal delay is typically reported in GHD patients especially in boys (Burns et al., 1981; Coutant and Carel, 2002). This delay is found in almost all the cases in our study. In agreement with the literature, it is more important for boys than for girls. Burns and al (Burns et al., 1981) found that the age of pubertal development in these patients was 15.9 years for boys and 12.7 years for girls. The comparison of pubertal development of patients in the study with those of the Marshall studies (Marshall and Tanner, 1970) and those of Maiza (1983) on Algerian healthy subjects showed that boys have an average onset puberty and later completion of puberty:  2.4 years (this study) vs. 12 (Marshall) and 12.16 years (Maiza)16.4 and 19.8 ± 2.2 years (this study) vs. 15.18 years (Marshall) and 16.16 ± 1 year (Maiza). However the course of puberty is normal and comparable to the results of Marshall (Marshall and Tanner, 1970; Maiza, 1983).

The same observations can be made for the girls. Average age of patients in the study at the beginning of puberty was 13.9 ± 2.8 years (vs. 11 years (Marshall) and 11.7 ± 1.33 year (Maïza)). The Age at the end of puberty was 17.4 ± 2.8 years (vs. 14.5 (Marshall) and 16.3 years (Maiza)). However, the time of the progress of puberty: 3, 1 ± 1.1 years was comparable to the results of Marshall (Marshall and Tanner, 1970) and Maiza (1983).

As regards the menarche, the average age is significantly delayed compared to Marshall 15.46 ± 2.00 vs. 13.47 ± 0.10 years (p <0.005) and Maiza 13.66 (P<0.05) (Carroll and Christ, 1998), and if we consider the secular advance of menarche, the noticed delay would be found even greater.

In fact, regardless of sex, puberty can be performed at a normal age when the diagnosis of GH is made and treatment is instituted early; this was found in ten patients in the study.

On the other hand, it should also be noted that if puberty is generally carried out normally, a reduction in the duration of the course of puberty may even (Bourguignon et al., 1986). This was observed in two patients in this study. This reduction in the duration of puberty is linked to the action of growth hormone on bone maturation. An advance of puberty may also be (Tobiume et al., 1997; Price and Heidelberg, 1999).

Currently, all authors would agree to say the role of diagnosis and early treatment with the GHr in the development of puberty. Indeed, GH plays a key role in gonadal function by inducing local production of IGF1 in the ovaries and testes which increases sex steroids production. The IGF1 promotes ovulation in females (Daftary and Gore, 2005).
Also, the lack of growth hormone IGF1 includes disrupting follicular development which could be the cause of ovarian disease (DOPK) in GHD patients whose frequency has been reported by some authors (Kazerr et al., 1990; Morales, 1997; Pienkowski et al., 2007).

This aspect of DOPK was found in five patients in the study who showed Spanio menorrheys with multiple ovarian sub-centimeter follicles in ultrasound.

The finding of DOPK in GH emphasizes the need for prevention of this complication by early and regular hormone substitution.

Moreover, it should be noted that the used strategies to optimize growth stature pubertal failed to consensus. Whether to increase GH doses in order to mimic the physiology of the pubertal growth (Blethen, 1997; Codner, 1997; Carel, 2004), or block puberty using similar LHRH (Hibi et al., 1989; Balducci et al., 1995; CASSORLA, 1997). The results are divergent. If Mauras et al. (1996) demonstrated that tripling the dose of GHr has increased the height gain of 4.6 cm. Other authors report on the contrary a lesser height gain due to the action of GH, which in promoting bone maturation, reduced pubertal growth (Bourguignon, 1988; Tanaka et al., 2002; Saenger, 2003).
Regarding the association of treatment with LHRH analogues GH, some authors (Frish and Birnbacher, 1995; Cassorla, 1997; Kohn et al., 1999) have sought to increase growth by slowing pubertal development.

The results of the final height differ according to the authors. The most important study is that of Cassorla (Balducc et al., 1995). By associating LHRH analogs with GHr during 03 consecutive years, he found a significant increase in adult height compared to those who received GHr alone (14.0 ± 1.6 cm vs 8.0 ± 2.4 cm, p <0.05). These results confirm those of Burns et al. (1981), Hibi et al. (1989),Frish and Birnbacher (1995) and Mericq et al. (2000).
 



 Table I The average height of patients GHD at diagnosis in both sexes

 



 Table II Results on the pubertal growth

 



 Table III Final herght of patients GHD who completed their puberty in both sexes


Other authors did not find this effect on the pubertal growth. In fact, the short study duration less than 02 years doesn’t permit evaluation of combined treatment (LHRH analogues and GHR) on the final size (Toublanc et al., 1989; Saggese et al., 2001). In practice, that protocol is envisaged in children with a very small size at puberty. This situation could have been considered in our patients. The size at puberty was also affected at diagnosis. The indication of this combination was not applied because of the constraints associated with these therapies and the prolonged duration of the protocol that must be maintained on at least five years to expect a final size acceptable (Price and Heidelberg, 1999). Nevertheless, the magnitude of the pubertal growth rate in GH treatment is unclear because very dependent on the clinical context: the severity of GH deficiency and its isolated nature or combined (Burns et al., 1981; Frasier et al., 1981; Hibi et al., 1989). It must, however, emphasize that the stature pubertal gain only 16% on average (11-21%) of the adult size (Pierson, 1986; Brauner, 1994). it was very poor for our patients and significantly different from the average theoretical value (14.7 ± 1.2 cm vs. 28 cm for males and 12.2 ± 1.9 cm vs. 25 cm in girls). The adult final height is closely related to the size at puberty. This is mainly influenced by the early diagnosis of GH and regular and effective therapy with GHr.

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