J. Endocrinol. Invest. 15: 777-781, 1992
REVIEW ARTICLE
Growth hormone deficiency throughout puberty A. Albanese and R. Stanhope The Institute of Child Health, London, UK /NTROOUCT/ON
MECHANlSM OF THE GROWTH SPURT
Although we have a reasonable assessment of the dose of growth hormone (GH) required in prepubertal children, it is unknown whether such dose regimens need to be varied as prepubertal growth proceeds from a "catch-up" phase to a restoration of normal growth rate. Certainly the dose of GH required should depend upon the size of the patient (1). A daily dose schedule provides a better rate of growth than a less frequent administration of injections (2). It is probable that injection regimens of greater than daily will not be more effective (3), despite the physiology of GH secretion (4) with an endogenous GH pulse frequency of approximately 3 hr. However, although it has been appreciated that GH pulse amplitude increases during the pubertal growth spurt (5), little is known about the necessity for an altered dose regimen during pubertal growth of children with GH deficiency, either isolated or associated with multiple pituitary hormone deficiency.
It is probable that a major contribution to the pubertal growth spurt is accorded by a dramatic increase in amplitude of GH secretory episodes in the presence of sex steroids (10). Indeed, it is the alteration in GH secretion, not in sex steroids (Fig. 1), which correlates with growth rate during puberty in both sexes (5). Undoubtedly sex steroids modulate the adolescent growth spurt, from the data of sex steroid "priming" of GH secretion (11), as weil as affecting the advancement of epiphyseal maturation. During puberty in boys there is a gradual rise of serum testosterone, and because the commencement of the growth spurt does not take place until considerable virilization has occurred, the effect of testosterone priming is probably related to a "threshold" of testosterone concentration. In addition to the effect on growth, GH also influences pubertal development by increasing local production of insulin-like growth factors both within the ovary (12) and testes (13) as weil as modulating the gonadal response to gonadotrophin secretion (14). For this reason GH has been used to facilitate ovulation induction by gonadotrophins in the human female (15). Both GH and sex steroids are required for the pubertal growth spurt. The absence of either (16) results in a greatly diminished magnitude of the growth spurt, thereby resulting in a compromised final height.
NORMAL PUBERTY ANO THE GROWTH SPURT
The onset of the spontaneous growth spurt of puberty and the stage of sexual maturation are intimately related, irrespective of chronological age (6). In girls (7) growth acceleration occurs early with the onset of breast development, whereas in boys (8) the rate of growth continues to decelerate at the onset of puberty and only accelerates later at the attainment of genitalia stage 3 to 4 (10 ml testicular volume). It may be that the increased sensitivity of the gonadotroph to gonadotrophinreleasing-hormone (GnRH) in girls (9) leads to an earlier onset of sexual maturation with a mean difference in onset of puberty between the sexes of 6 months.
F/NAL HE/GHT OF CH/LOREN W/TH /SOLA TED GH OEF/C/ENCY
Historical data has suggested that there is an important relationship between growth hormone and sex steroids (17). Although the data analysis was retrospective, children with multiple pituitary hormone deficiency treated with both androgens and GH progressed through puberty twice as fast as those who were treated only with androgens. However final height attainment was si milar in the two groups. In addition, there is other evidence (18) which suggests that there may be an important interaction between GH and testos-
Key-words: Growth hormone, puberty, growth spurt. dose 01 growth hormone. Correspondence: Dr R. Stanhope. The Medical Unit, The Institute 01 Child Health, 30 Guilford Street, London WC1N 1EH.
777
A. Albanese, R. Stanhope
BOY: ACE 1III.0yrs
Tuticu lar Vol. ml5
11
12
G. V. cm/y r
10
11
20 [
Tnle,tll!!!""". \0 nmol/L
o~ 20
eH ",U / L
10~ 20
01
06
20
01
06 20
01
06
20
06
01
( lOCk time
Figure 1 - Serum testosterone and GH profi/es from a 14.0 years old boy treated with pu/satile GnRH in order to mimic norma l puberty Profiles were obtained pretreatment and at 3, 10 and 14 months of treatment. Height velocity corresponding to mean testicular vo/ume is shown corresponding to each profile. GH se cre tion and growth velocity initially decreased. inspite of an increased testosterone secreIion. From Stanhope et al. (5) with perrnission
DOSE OF EXOGENOUS GH DURING PUBERTY
terone at a peripherallevel , as weil as in the gonad. In patients with isolated GH deficiency treated with GH (19-21) there was a delay in the onset of pubertal maturation but epiphyseal maturation was appropriate. Total duration of puberty was shorter than in normal boys and there was a significant correlation between final height and height at the onset of puberty. This points to growth in earlier childhood being important for final height attainment, rather than a possible failure of treatment during puberty. Consequently optimum outcome depends on early diagnosis. Hibi et al. (22) described 108 patients with isolated GH deficiency who had a final height related to height SDS at the onset of treatment as weil as at the onset of pubertal maturation. In addition, there was a positive correlation between chronological age at the onset of puberty and chronological age at commencement of treatment.
Several attempts have been made during the pu berty of GH deficient children to improve growth and ultimately final height by altering the dose of GH. Indeed it has been common practice in some centres (24) to double the dose of GH during puberty. Although this may mimic the normal physiology (4), little evidence has been obtained that this 100
(a) Girls
.
-----_.,-
:....~::.;:.:;:~J- J
80
: :
l
- -,
~-j
60 40 20
2 100
PUBERTAL MA TURA TION DURING GH TREATMENT
(b)
3
- r ----.".·"r· .. ~ .........• : ..... : .
Boys
80 60
Further evidence has been accumulated which indicates that GH administered in conventional regimens for the treatment of isolated GH deficiency may interfere with the normal progression of pubertal maturation. Darendeliler et al. (23) found a significant delay at the onset of puberty in 134 children with isolated GH deficiency during GH treatment. In addition the duration of pubertal maturation was significantly shortened, which indicates that GH may accelerate pubertal maturation (Fig. 2). This is similar to other Authors (20) who described an acceleration of bone maturation during the puberty of GH deficient children.
5
....
%
40 : .....
20
0
2
3
5
Figure 2 - Rate of pubertal progression in girls (82 to 84) and boys (G2 to G4) in 134 children with isolated GH deficiency on growth hormone therapy Cumulative percentage of girls/boys having progressed through puberty at given interval in years Oata for GH deficient children are shown in the solid lille. whereas normal data is shown in the broken fines. From Oarendeliler el a/. (23) with permission
778
GH deficiency throughout puberty
n=
o
26 20
26 20 19 12
16 10
6 9
26 19
26 20
-1 Height SDS
-2
ns ns
-3 After At random 1 yr -isation
ns ns
ns
After 2 yrs
After 3 yrs
ns ~ 15 U/m2 /wk ['/':-',:··1 30 U/m2/wk
After Pred Mid4 yrs Heig ht parental Random height -isation
is beneficial in terms of final height attainment. Stanhope et al. (25, 26) have investigated this possibility by randomising their patients at the commencement of the growth spurt into two groups, receiving either an unaltered or double dose of growth hormone. There was no significant improvement in growth rate using a regimen of 30 units/m 2/wk compared with 15 units/m 2/wk, with no alteration in height SOS (Fig. 3) after 4 yr. However there was a rapid progression through puberty and this was probably dose related (Fig. 4). In 1987, Job et al. (27) demonstrated a lack of correlation during puberty between GH dose and growth rate, although most patients received only 0.3 units/kg/wk with little variation between patients. Such observations may have important implications for the treatment of children with idiopathic GH deficiency with growth hormone. Indeed, final height prognosis may even deteriorate with a rapid advancement of epiphyseal maturation, without a corresponding improvement in growth rate. Four-yr data from the study of Stanhope et al. (25, 26) suggest that there is no significant difference in height prognosis between two GH dose regimens after 3 yr from the dose randomisation (breast stage 2 in girls; 6 to 8 ml testicular volume in boys) (Fig. 5). Indeed the data from the first two years suggest a decrease, although not significant, in the group treated with the high dose regimen. Oata at 3 yr (Fig. 5) is difficult to interpret as the numbers are small. A further therapeutic approach would be to use a gonadotrophin releasing hormone analogue to delay the on set of, or to increase the duration of, spontaneous puberty with the aim of delaying the rate of bane age maturation. Of course such a therapeutic approach may have additional psycholog-
Figure 3 - Height SOS during the first 4 yr of the study of Stanhope et al. (25,26) in ehildren with isolated GH defieieney randomised at the onset of the growth spurt to either 15 or 30 lU/m 2/wk given as a daily subeutaneous injeetion ns = not signifleant: n = number of patients. One standard deviation is shown
ical sequelae as a consequence of further pubertal delay. An interesting model of the effect of delayed pubertal maturation on final height, is the growth of GH insufficient children who also have gonadotrophin insufficiency (20, 21). Final height of such children was greater than those with isolated
-
-
G5 ,----
~
G4 -
~
G3 ~
G2 10
11
12
13
14
15
16
Age in years Figure 4 - Progress through puberty of 25 boys with isolated idiopathie GH defieieney randomised into either 15 lU/m 2/wk (open eireles) or a double dose of 30 IU/m 2/wk (solid eire/es) at the onset of the growth spurt (6 to 8 ml testieular volume). The eontmuous line represents the mean age at the onset of eaeh stage of puberty in normal boys (8). The vertieal bars represent 1 SO From Stanhope et al. (25) with permission
779
A. Albanese, R. Stanhope
n=
0
26 19
22 14
-0.5 Heist'lt.~ 0
SDS
I.
for -1.5
Bol"
-.2.0
ns
-2.5
At Rar.c1omisation
ns 1st
Yee.r·
ns
m~ 15 U/rrr-iwk mf»~ ~'O U/rrf-l'ilik
2nd Year
3rd
Vear
Figure 5 - Height for bone age SOS as an assessment of height prognosIs from the study by Stanhope et al. (25, 26) for the first three yr from randomisation of the GH dose regimen. The re was neither a signiflcant dtfference (ns) in heigh t p rogno sIs between the two groups, nor any overall improvement n = number of patients. One SO is shown .
REFERENCES
GH deficiency. However one disadvantage of the induction of late pubertal maturation (age 18 to 20 yr) was the attainment of eunuchoid body disproportion (20) with a relatively short spine. Preliminary results have been reported of the effectiveness of the combination of GH with gonadotrophin releasing hormone analogue (28) or cyproterone acetate (29) in pubertal patients with isolated GH deficiency. The dual endocrinopathy of premature puberty and growth hormone insufficiency induced by low-dose cranial irradiation has been treated with a combination of GH and GnRH analogue (30) . Such a combined treatment regimen has produced a progressive improvement in height prognosis during 4 yr of th erapy.
1. Fras ier SD. , Costin G, Lippe BM , Aceto T , Bun ger
PF
Dose resp onse curve for human growth hormone . J. Clin. En docrinol. Metab . 53.1213 , 1981 2. Albert sson-Wikland K , Westphal 0 , Westgren U Daily subc utaneou s admini stration of hum an growth hormone in growth horm one defi cient children. Ac ta Paediatr. Scand . 75.89, 1986. 3. Hin dmarsh pe, Stanhope R, Pre ece M A . Brook
C.G D.
4.
SUMMARY
5.
Growth during puberty does not appear to be the major determinate of final height in isolated GH deficient patients. Early diagnosis and commencement of therapy are probably the most important factors , as reflected by the correlation between final height and height at the onset of puberty. The cost effectiveness of increasing the dose of GH du ring puberty does not appear to represent any advantage from the data presentlyavailable. Indeed , such an approach may have a deleterious effect on final height by shortening the duration of pubertal maturation. Further prospective studies are required to demonstrate the effectiveness of manipulating the onset and duration of puberty using gonadotrophin releasing hormone analogues on final height in isolated GH deficiency.
6.
7.
8.
9.
ACKNOWLEDGMENTS 10.
Dr Alb ane se was supp orted by a grant Irom Eli Lilly UK. Financ ial as sistance was obta ine d Irom Se rono UK lor the preparation 01 th is manusc ript.
780
Freq uency of admini stration of growth hormone - an important factor in determining growth response to exogenou s growth horm one. Hormone Res. 33 (suppl 4). 83, 1990. Brook CGD. , Hin dmarsh pe, Stanhop e R. Growth and growth hormone sec reti on: a rev iew. J. Endoc rin ol. 119. 179,1 988 . Stanhope R, Pringle PJ. , Brook e GD. The mechanism of the adolescent growth spurt induce d by low-dose pulsatile GnRH treatment. Clin . Endocrinol. 28. 83,1988. Stanhope R , Brook C.G. Th e c linical diagnos is of disord ers of puberty th e loss of conso nance. Br. J. Hosp Med. 35.' 57 , 1986. Marshall WA, Tann er J.M. Variations in the pattern of p ubertal changes In girls Arch. Dis. Child . 44. 29 1, 1969. Marshall WA , Tann er J.M. Variati ons in the pattern of pubertal chan ges In boys Arch. Dis. Child. 45.' 13, 1970. Stanhope R , Brook C.GD, Pringl e PJ , Adams J , Jacobs H.S . Induction of puberty by pulsatile gonad otrophi n re leasing hormone. Lancet ii. 552 , 1987. Mauras N , Blizzard R.M ., Link K , John so n M. L, Rogol AD. , Veldhui s JD. Augmentation of growth hormon e sec retio n durin g
GH deficiency throughout puberty
puberty: evidence for a pulse amplitude-modulated phenomenon. J. Clin. Endocrinol. Metab. 64.596,1987. 11. Drop SL, Sabbe-Claus L., Visser H.KA The effect of puberty and short-term oral administration of testosterone undecanoate on GH tests and sex steroid related plasma compounds in GH deficient patients. Clin. Endocrinol. 16: 375,1982.
22.
23.
12. Davoren J.B., Hsueh J W. Growth hormone increases ovarian levels of immunoreactive somatomedin C/insulin-like growth factor I in vivo. Endocrinology 118.' 888, 1986.
24.
13. Tres L.L., Smith E, Van Wyk J.J., Kierszenbaum AL. Somatomedin-C in rat Sertoli-spermatogenic cell cocultures. J. Cell. Biol. 97' 18a, 1983. 14. Adashi E.Y, Resnick CE, D'Ercole AJ, Svoboda ME, Van Wyk J.J. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr. Rev. 6. 400, 1985.
25.
26.
15. Homburg R., Eshel A, Abdalla H I, Jacobs H.S. Growth hormone facilitates ovulation induction by gonadotrophins. Clin. Endocrinol. 29.113,1988. 16. Aynsley-Green A, Zachmann M., Prader A Inter-relation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism. J. Pediatr. 89.' 992,1976. 17. Van der Werff ten Bosch J.J, Bot A Does hGH treatment promote adult height of hypopituitary children? J. Med. 32.217,1988. 18. Zachmann M., Prader A Anabolic and androgenic effect 01 testosterone in sexually immature boys and its dependency on growth hormone. J. Clin. Endocrinol. Metab. 30. 85,1970. 19. Price DA, Shalet S.M., Clayton PE Management 01 idiopathic growth hormone deficient patients during puberty. Acta Paediatr. Scand. (suppl) 347 44,1988. 20. Burns E.C., Tanner J.M., Preece MA, Cameron N. Final height and pubertal development in 55 children with idiopathic growth hormone deficiency treated lor between 2 and 15 years with human growth hormone. Eur. J. Paediatr. 137: 155,1981.
27.
28.
29.
30.
21. Bourguignon JP., Vandewegh M., VanderschuerenLodeweycx M, Malvaux P., Wolter R, Du Caju M, Ernould C.
781
Pubertal growth and final height in hypopituitary boys: a minor role of bone age at onset 01 puberty. J. Clin. Endocrinol. Metab. 63: 376, 1986. Hibi I, Tanaka T. Final height of patients with idiopathic growth hormone deliciency after long-term growth hormone treatment. Acta Endocrinol. 120: 409,1989. Darendeliler F., Hindmarsh PC., Preece MA, Cox L., Brook C.G D. Growth hormone increases rate 01 pubertal maturation. Acta Endocrinol. 122:414,1990. Vanderschueren-Lodeweyckx M., van den Broeck J, Wolter R., Malvaux P. Early initiation of growth hormone treatment: inlluence on final height. Acta Paediatr. Scand. (suppl.) 337: 4, 1987. Stanhope R., Uruena M., Hindmarsh P, Leiper AD., Brook C.G.D. Management of growth hormone deficiency through puberty. Acta Paediatr. Scand. (suppl.) 372: 47, 1991. Stanhope R, Albanese A, Hindmarsh P.C., Brook CG.D. The effects of growth hormone therapy on spontaneous sexual development. Hormone Res. (in press), 1992. Job J.C, Chaussain J-L., Garnier P., Rolland A., Joab N. Dose-response relationship in the treatment of hypopituitary children with human growth hormone: a retrospective survey. Acta Paediatr. Scand. (suppl.) 337: 93,1987. Toublanc JE, Couprie C, Garnier P, Job J.C. The effects of treatment combining an agonist 01 gonadotrophin-releasing hormone with growth hormone in pubertal patients with isolated growth hormone deficiency. Acta Endocrinol. 120. 795, 1989. Hibi I, Takana T., Tanae A, Kagawa J., Hashimoto N., Yoshizawa A, Shizume K. The influence 01 gonadal function and the effect of gonadal suppression treatment on final height in growth hormone (GH) treated GH delicient children J. Clin. Endocrinol Metab. 69: 221, 1989. Stanhope R., Papadimitriou A., Chessells J.M., Leiper AD. Precocious and premature puberty following prophylactic irradiation in acute Iymphoblastic leukaemia. In: Green D. (Ed.), Late effects 01 treatment for childhood cancer. Wiley-Liss Inc, New York, 1992, p. 89.
REVIEW ARTICLE
Growth hormone deficiency throughout puberty A. Albanese and R. Stanhope The Institute of Child Health, London, UK /NTROOUCT/ON
MECHANlSM OF THE GROWTH SPURT
Although we have a reasonable assessment of the dose of growth hormone (GH) required in prepubertal children, it is unknown whether such dose regimens need to be varied as prepubertal growth proceeds from a "catch-up" phase to a restoration of normal growth rate. Certainly the dose of GH required should depend upon the size of the patient (1). A daily dose schedule provides a better rate of growth than a less frequent administration of injections (2). It is probable that injection regimens of greater than daily will not be more effective (3), despite the physiology of GH secretion (4) with an endogenous GH pulse frequency of approximately 3 hr. However, although it has been appreciated that GH pulse amplitude increases during the pubertal growth spurt (5), little is known about the necessity for an altered dose regimen during pubertal growth of children with GH deficiency, either isolated or associated with multiple pituitary hormone deficiency.
It is probable that a major contribution to the pubertal growth spurt is accorded by a dramatic increase in amplitude of GH secretory episodes in the presence of sex steroids (10). Indeed, it is the alteration in GH secretion, not in sex steroids (Fig. 1), which correlates with growth rate during puberty in both sexes (5). Undoubtedly sex steroids modulate the adolescent growth spurt, from the data of sex steroid "priming" of GH secretion (11), as weil as affecting the advancement of epiphyseal maturation. During puberty in boys there is a gradual rise of serum testosterone, and because the commencement of the growth spurt does not take place until considerable virilization has occurred, the effect of testosterone priming is probably related to a "threshold" of testosterone concentration. In addition to the effect on growth, GH also influences pubertal development by increasing local production of insulin-like growth factors both within the ovary (12) and testes (13) as weil as modulating the gonadal response to gonadotrophin secretion (14). For this reason GH has been used to facilitate ovulation induction by gonadotrophins in the human female (15). Both GH and sex steroids are required for the pubertal growth spurt. The absence of either (16) results in a greatly diminished magnitude of the growth spurt, thereby resulting in a compromised final height.
NORMAL PUBERTY ANO THE GROWTH SPURT
The onset of the spontaneous growth spurt of puberty and the stage of sexual maturation are intimately related, irrespective of chronological age (6). In girls (7) growth acceleration occurs early with the onset of breast development, whereas in boys (8) the rate of growth continues to decelerate at the onset of puberty and only accelerates later at the attainment of genitalia stage 3 to 4 (10 ml testicular volume). It may be that the increased sensitivity of the gonadotroph to gonadotrophinreleasing-hormone (GnRH) in girls (9) leads to an earlier onset of sexual maturation with a mean difference in onset of puberty between the sexes of 6 months.
F/NAL HE/GHT OF CH/LOREN W/TH /SOLA TED GH OEF/C/ENCY
Historical data has suggested that there is an important relationship between growth hormone and sex steroids (17). Although the data analysis was retrospective, children with multiple pituitary hormone deficiency treated with both androgens and GH progressed through puberty twice as fast as those who were treated only with androgens. However final height attainment was si milar in the two groups. In addition, there is other evidence (18) which suggests that there may be an important interaction between GH and testos-
Key-words: Growth hormone, puberty, growth spurt. dose 01 growth hormone. Correspondence: Dr R. Stanhope. The Medical Unit, The Institute 01 Child Health, 30 Guilford Street, London WC1N 1EH.
777
A. Albanese, R. Stanhope
BOY: ACE 1III.0yrs
Tuticu lar Vol. ml5
11
12
G. V. cm/y r
10
11
20 [
Tnle,tll!!!""". \0 nmol/L
o~ 20
eH ",U / L
10~ 20
01
06
20
01
06 20
01
06
20
06
01
( lOCk time
Figure 1 - Serum testosterone and GH profi/es from a 14.0 years old boy treated with pu/satile GnRH in order to mimic norma l puberty Profiles were obtained pretreatment and at 3, 10 and 14 months of treatment. Height velocity corresponding to mean testicular vo/ume is shown corresponding to each profile. GH se cre tion and growth velocity initially decreased. inspite of an increased testosterone secreIion. From Stanhope et al. (5) with perrnission
DOSE OF EXOGENOUS GH DURING PUBERTY
terone at a peripherallevel , as weil as in the gonad. In patients with isolated GH deficiency treated with GH (19-21) there was a delay in the onset of pubertal maturation but epiphyseal maturation was appropriate. Total duration of puberty was shorter than in normal boys and there was a significant correlation between final height and height at the onset of puberty. This points to growth in earlier childhood being important for final height attainment, rather than a possible failure of treatment during puberty. Consequently optimum outcome depends on early diagnosis. Hibi et al. (22) described 108 patients with isolated GH deficiency who had a final height related to height SDS at the onset of treatment as weil as at the onset of pubertal maturation. In addition, there was a positive correlation between chronological age at the onset of puberty and chronological age at commencement of treatment.
Several attempts have been made during the pu berty of GH deficient children to improve growth and ultimately final height by altering the dose of GH. Indeed it has been common practice in some centres (24) to double the dose of GH during puberty. Although this may mimic the normal physiology (4), little evidence has been obtained that this 100
(a) Girls
.
-----_.,-
:....~::.;:.:;:~J- J
80
: :
l
- -,
~-j
60 40 20
2 100
PUBERTAL MA TURA TION DURING GH TREATMENT
(b)
3
- r ----.".·"r· .. ~ .........• : ..... : .
Boys
80 60
Further evidence has been accumulated which indicates that GH administered in conventional regimens for the treatment of isolated GH deficiency may interfere with the normal progression of pubertal maturation. Darendeliler et al. (23) found a significant delay at the onset of puberty in 134 children with isolated GH deficiency during GH treatment. In addition the duration of pubertal maturation was significantly shortened, which indicates that GH may accelerate pubertal maturation (Fig. 2). This is similar to other Authors (20) who described an acceleration of bone maturation during the puberty of GH deficient children.
5
....
%
40 : .....
20
0
2
3
5
Figure 2 - Rate of pubertal progression in girls (82 to 84) and boys (G2 to G4) in 134 children with isolated GH deficiency on growth hormone therapy Cumulative percentage of girls/boys having progressed through puberty at given interval in years Oata for GH deficient children are shown in the solid lille. whereas normal data is shown in the broken fines. From Oarendeliler el a/. (23) with permission
778
GH deficiency throughout puberty
n=
o
26 20
26 20 19 12
16 10
6 9
26 19
26 20
-1 Height SDS
-2
ns ns
-3 After At random 1 yr -isation
ns ns
ns
After 2 yrs
After 3 yrs
ns ~ 15 U/m2 /wk ['/':-',:··1 30 U/m2/wk
After Pred Mid4 yrs Heig ht parental Random height -isation
is beneficial in terms of final height attainment. Stanhope et al. (25, 26) have investigated this possibility by randomising their patients at the commencement of the growth spurt into two groups, receiving either an unaltered or double dose of growth hormone. There was no significant improvement in growth rate using a regimen of 30 units/m 2/wk compared with 15 units/m 2/wk, with no alteration in height SOS (Fig. 3) after 4 yr. However there was a rapid progression through puberty and this was probably dose related (Fig. 4). In 1987, Job et al. (27) demonstrated a lack of correlation during puberty between GH dose and growth rate, although most patients received only 0.3 units/kg/wk with little variation between patients. Such observations may have important implications for the treatment of children with idiopathic GH deficiency with growth hormone. Indeed, final height prognosis may even deteriorate with a rapid advancement of epiphyseal maturation, without a corresponding improvement in growth rate. Four-yr data from the study of Stanhope et al. (25, 26) suggest that there is no significant difference in height prognosis between two GH dose regimens after 3 yr from the dose randomisation (breast stage 2 in girls; 6 to 8 ml testicular volume in boys) (Fig. 5). Indeed the data from the first two years suggest a decrease, although not significant, in the group treated with the high dose regimen. Oata at 3 yr (Fig. 5) is difficult to interpret as the numbers are small. A further therapeutic approach would be to use a gonadotrophin releasing hormone analogue to delay the on set of, or to increase the duration of, spontaneous puberty with the aim of delaying the rate of bane age maturation. Of course such a therapeutic approach may have additional psycholog-
Figure 3 - Height SOS during the first 4 yr of the study of Stanhope et al. (25,26) in ehildren with isolated GH defieieney randomised at the onset of the growth spurt to either 15 or 30 lU/m 2/wk given as a daily subeutaneous injeetion ns = not signifleant: n = number of patients. One standard deviation is shown
ical sequelae as a consequence of further pubertal delay. An interesting model of the effect of delayed pubertal maturation on final height, is the growth of GH insufficient children who also have gonadotrophin insufficiency (20, 21). Final height of such children was greater than those with isolated
-
-
G5 ,----
~
G4 -
~
G3 ~
G2 10
11
12
13
14
15
16
Age in years Figure 4 - Progress through puberty of 25 boys with isolated idiopathie GH defieieney randomised into either 15 lU/m 2/wk (open eireles) or a double dose of 30 IU/m 2/wk (solid eire/es) at the onset of the growth spurt (6 to 8 ml testieular volume). The eontmuous line represents the mean age at the onset of eaeh stage of puberty in normal boys (8). The vertieal bars represent 1 SO From Stanhope et al. (25) with permission
779
A. Albanese, R. Stanhope
n=
0
26 19
22 14
-0.5 Heist'lt.~ 0
SDS
I.
for -1.5
Bol"
-.2.0
ns
-2.5
At Rar.c1omisation
ns 1st
Yee.r·
ns
m~ 15 U/rrr-iwk mf»~ ~'O U/rrf-l'ilik
2nd Year
3rd
Vear
Figure 5 - Height for bone age SOS as an assessment of height prognosIs from the study by Stanhope et al. (25, 26) for the first three yr from randomisation of the GH dose regimen. The re was neither a signiflcant dtfference (ns) in heigh t p rogno sIs between the two groups, nor any overall improvement n = number of patients. One SO is shown .
REFERENCES
GH deficiency. However one disadvantage of the induction of late pubertal maturation (age 18 to 20 yr) was the attainment of eunuchoid body disproportion (20) with a relatively short spine. Preliminary results have been reported of the effectiveness of the combination of GH with gonadotrophin releasing hormone analogue (28) or cyproterone acetate (29) in pubertal patients with isolated GH deficiency. The dual endocrinopathy of premature puberty and growth hormone insufficiency induced by low-dose cranial irradiation has been treated with a combination of GH and GnRH analogue (30) . Such a combined treatment regimen has produced a progressive improvement in height prognosis during 4 yr of th erapy.
1. Fras ier SD. , Costin G, Lippe BM , Aceto T , Bun ger
PF
Dose resp onse curve for human growth hormone . J. Clin. En docrinol. Metab . 53.1213 , 1981 2. Albert sson-Wikland K , Westphal 0 , Westgren U Daily subc utaneou s admini stration of hum an growth hormone in growth horm one defi cient children. Ac ta Paediatr. Scand . 75.89, 1986. 3. Hin dmarsh pe, Stanhope R, Pre ece M A . Brook
C.G D.
4.
SUMMARY
5.
Growth during puberty does not appear to be the major determinate of final height in isolated GH deficient patients. Early diagnosis and commencement of therapy are probably the most important factors , as reflected by the correlation between final height and height at the onset of puberty. The cost effectiveness of increasing the dose of GH du ring puberty does not appear to represent any advantage from the data presentlyavailable. Indeed , such an approach may have a deleterious effect on final height by shortening the duration of pubertal maturation. Further prospective studies are required to demonstrate the effectiveness of manipulating the onset and duration of puberty using gonadotrophin releasing hormone analogues on final height in isolated GH deficiency.
6.
7.
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ACKNOWLEDGMENTS 10.
Dr Alb ane se was supp orted by a grant Irom Eli Lilly UK. Financ ial as sistance was obta ine d Irom Se rono UK lor the preparation 01 th is manusc ript.
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