Constitutional Delay of Growth and Adolescent ... - GGH Journal

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Constitutional Decay Of Growth II. These data indicate that pa- Growth, Genetics, and Hormones, And Adolescent Development tients with CDGAD secrete less Vol. 1, No.4). continued from page 9 GH at all stages of pubertal devel- At least three groups of investi- opment than do control children. gators have reported increased els.o! less th~n 3 ng/ml. The re- Differences between the patients and controls were statistically sig- IGF-I levels in tall children (compared with children of normal statmalnlng 24 children were betwe~n nificant in all groups, except for ure); others have reported de- 11 and 15 years of age and In those in stage 2 of sexual devel- creased IGF-I values in short pubertal stages 1 and 2. Their opment. The interpretation of children (compared with children peak GH levels were 3 to 8 ng/ml. these data prompts the hypothesis of normal size).19-21 Children with Ten of. these 24 were retested after that there is permanently dimin- CDGAD have IGF-I values in acreaching stage 3 of sexual devel- ished GH secretion. cord with their skeletal maturation opment, a~d they had peak GH A second form of growth delay, rather than with their chronological concentrations of between 8 and which is designated as "short stat- age. Link et al22 demonstrated that 45 ng/ml, with a mean of 21 ng/ml. The authors interpreted these observations as indicative of t" htran~~;-~~-P hartial GbHD." dOthedr au- Table II. Sleep-Induced GH Secretion in 124 Patients With CDGAD and 28 ors ..av.e 0 serv~ an. re- Controls ported similar Instances In patients who appear to have GHD pre- Puberty stages pubertally but who have normal P1 P2 P3 respo~ses to provocative tests (Number of cases) (86) (18)t (31) (3.)f (7) (7)t following the onset of puberty. Sleep-induced It is probably incorrect, how- GH secretion 2469** 4349 3347 5905 3580** 9794 ever, to compare normal values 5V2 hrs :t 1068 :t 1134 :t 1619 -:t 1633 :t 1711 obtained after the onset of puberty (ng/ml x 330 min) with the normal values found in prepubertal children. The mean Peak GH level 22.5*' 38.8 27.2 49.8 21.2' 66.2 stimulated values in normal ado- :t 8.1 :t 27.0 Ie scents are approximately twice those of prepubertal children. With 'Statistically significant difference v controls P > 001 stimulation, patients with CDGAD "Statistically significant difference v controls P > 0.001 reportedly do not have GH peaks tControl children of the same magnitude as do normal children during puberty. Because of the variability of results obtained after pharma- ure due to an immunologically re- the administration of testosterone cologic stimuli, several au- active but biologically inactive to these patients increased both thors5.11-13 have examined the GH," is sometimes clinically indis- GH production and IGF-llevels. It spontaneous secretion of GH tinguishable from CDGAD. In this is on this basis, as well as upon the throughout the day or night or entity, growth retardation is pre- observation that IGF-I levels inaround the clock. In only a few sumed to result from the produc- crease early in puberty, that one instances were abormally low tion of a GH molecule that is bio- may hypothesize that testosterone peaks found during sleep, eg, in logically inactive, since the GH increases the circulating concentwo of 14 patients reported by levels are normal or high and IGF-I trations of GH and the generation Wise and colleagues.13 In 1979, is low as in GH-deficient children. of IGF-I in early adolescence. and again in 1985, Bierich and However, patients with this entity, co-workers14.15 investigated sleepinduced GH secretion. The which was described by Hayek and co-workers 16 and Kowarski et The Need for Therapy The need for therapy and the results in children with CDGAD al,17 are usually more severely re- treatment chosen should be conwere compared with those in tarded in growth than are patients sidered for each individual ch,ild. healthy controls with equivalent with CDGAD. Subsequent patients The adult stature eventually sexual maturation. These investi- also have been described by reached by children with CDGAD gators determined the area under Bierich et al,4 Rudman and co- varies considerably and is related the GH-v-time curve to obtain the workers,1 and Valenta et al. 18 The to the heights of the parents. The integrated total secretion over 5.5 only attempt to determine the majority of patients attain a height hours at night. The highest peak structure of GH was made by within the normal range, unless. levels were also determined. The Valenta et al,18 who proposed a they are in the small/delay catresults obtained from 124 patients circulating GH molecule of ab- egory. Nevertheless, Preece and and 28 controls are shown in Table normal structure. (See abstract in colleagues23 first demonstrated
that the adult height of those with The use of testosterone is lim- GH of patients with CDGAD should CDGAD is below the mean for the ited to boys, usually 14 years of be reserved for the most severely general population. This was con- age and over, who have signifi- dwarfed children. Additional studfirmed by Ranke et al.24 Whether cant concern about their delayed ies under controlled conditions are therapy will increase ultimate sexual development. Martin and urgently required before GH height or whether it will affect only co-workers26 showed that doses treatment-outside of centers the rate of growth during treatment of 50 mg of a long-acting testos- where the efficacy of GH treatment is a question of great importance. terone ester (testosterone en- in patients who are not GH- If testosterone or androgens are anthate) once a month will en- deficient is being studied-can be used, one must consider whether hance sexual development recommended for patients with adult height may be reduced. without affecting adult height. CDGAD. Treatment certainly is indicated in Doses of 100 mg or greater very The use of other agents, such many patients and, in particular, in possibly reduce the ultimate as growth-hormone-releasing adolescent boys who are psycho- stature. Treatment is often con- hormone (GHRH) and clonidine, logically less able to cope with tinued for six to 12 months, an alpha2 adrenergic drug that their shortness, their delayed sex- at which time the testosterone stimulates the release of GH, reual maturation, and their high- is discontinued to determine quires further study. Results evalpitched voices. At no other time in whether spontaneous puberty uating GHRH in the treatment of childhood is the height gap with has occurred. Occasionally, a CDGAD have not been reported. relation to age mates as great as it repeat course of therapy begin- In 1985, Pintor et al29 administered is during early adolescence, par- ning six months after the end of clonidine to four patients with ticularly since the growth rate of the first course is appropriate. CDGAD over a period of two children with CDGAD reaches its months, and they described innadir at the same time that the Treatment with GH creased values of circulating GH adolescent growth spurt occurs in Studies evaluating GH for the and IGF-I and accelerated growth. normal children of the same age. treatment of CDGAD are few in However, this is an exceedingly Treatment should be seriously number. The first report of the suc- small series of patients treated for considered for patients who are in cessful administration of GH to a short period of time. Currently, danger of developing a severe in- such patients was from Grunt et al several investigators are involved feriority complex. One of two forms in 1972,27 who stimulated growth in studying the effect of clonidine of therapy can be chosen: the use in four of ten children with CDGAD. in CDGAD further. of testosterone with or without an- In a subsequent report by Kastrup abolic steroids, or the use of GH. et al,8 growth velocity rose from 3.7 Summary to 8.4 cm/year during therapy. CDGAD is the most common form Therapy With Testosterone Bierich and co-workers4 in 1983 of short stature. Preliminary studand/or Anabolic Steroids reported an increased growth rate ies suggest that children with Testosterone and/or anabolic (from 4.1 cm/year to 8.3 cm/year) CDGAD have inadequate GH prosteroids have been employed for with therapy. Gertner and co- duction, whereas children of the many years to treat CDGAD. The workers28 have reported similar same age who do not have anabolic steroids are derived findings. Individual differences are CDGAD, have adequate GH profrom testosterone. With the pos- considerable, but the greater the duction. Some would call this a sible exception of oxandrolone delay in bone age, the better the physiological state (partial GHD). (Anavar), all anabolic steroids acceleration of growth velocity. In this sense, CDGAD is similar to display similar androgenic or The growth rate in children with the previously described GHNSD. virilizing effects-including in- CDGAD had been maximal during Testosterone, and probably estrocreased skeletal maturation- the first year of treatment and de- gen as well, stimulates increased in comparison with testoster- creased thereafter, a pattern that production and secretion of GH. one. However, oxandrolone has occurs with GH-deficient patients This, in turn, stimulates increased a significant growth-promoting receiving GH. IGF-I concentrations in normal effect in relation to its minimal, Although adequate data are early puberty. modest virilizing action. At a presently unavailable to evaluate The use of GH as a therapeutic dosage of 0.1 mg/kg/day, oxan- the long-term effect of GH treat- agent in CDGAD is under clinical drolone has been used suc- ment on children with CDGAD, this investigation. Currently, oxancessfully in patients between the author has the clinical impression drolone (0.1 mg/kg/day) is the ages of 11 and 16 who are more that the growth prognosis of most treatment of choice in patients unconcerned about their height of these children improves. Since der 14 years of age who require a than their delayed sexual devel- none of the patients in our series growth-promoting agent for priopment. In Europe, Stanhope has reached final height, no defin- marily psychological reasons. Deand Brook25 reported favorable itive statements can be made re- potestosterone (long-acting enresults with oxandrolone in 24 garding an increase in ultimate anthate or cypronate) is the boys with CDGAD. height. At present, treatment with continued on page 12
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