Acta PEdiatr Scand [Suppl] 367: 119-125, 1990

REVIEW PAPER The Endocrinology of the Pubertal Growth Spurt O.H. PESCOVITZ From the Indiana University Medical Center, James Whitcomb Riley Hospital for Children Indianapolis, USA I

Puberty is a transitional stage from the sexually immature to the sexually mature state. It is accompanied by significant changes in hormonal activity, secondary sexual characteristics, behaviour, and growth velocity. The relative importance of each factor is most likely to depend on the developmental stage. There are two significant differences between pubertal and prepubertal growth: first, the rate of pubertal growth is usually 1.5-2 times greater; secondly, there is more dramatic maturation of the skeleton during pubertal growth. This review will evaluate the hormonal factors responsible for pubertal growth by examining paediatric endocrine conditions (1-5). PUBERTAL GROWTH SPURT AND FINAL ADULT HEIGHT In isolated hypogonadotropic hypogonadism, adrenarche occurs normally and gonadarche is delayed until hormonal therapy is initiated. However, there is some controversy about growth patterns in these patients. Several studies report normal growth in males with isolated hypogonadotropic hypogonadism, but the subjects were still growing at the time of reporting and, therefore, final adult height was not assessed (6-8). In a study of Czechoslovakian men with this disorder, the mean adult height was 4.0 cm greater than in a group of normospermic adult men being evaluated because of infertility (8). In a retrospective analysis of 41 patients with isolated hypogonadotropic hypogonadism who were untreated until a mean age of 20.0 years, final adult height exceeded the normal American standard by 5.6 cm and exceeded mean individual target height by 4.7 cm (9). Thus, in hypogonadotropic hypogonadism, the absence of gonadal sex steroids results in pubertal delay, a delay in pubertal growth spurt and probably a small, but significant, increase in final adult stature. Constitutional delay of growth and puberty is a complex, but more common, cause of delayed puberty. Typically, children with this condition are of short stature and delayed pubertal onset. When spontaneous hypothalamic-pituitary-gonadal activation occurs (sometimes as late as 17 or 18 years of age), the pubertal growth spurt is of normal magnitude and the final height is genetically appropriate. There has been great controversy as to whether androgen therapy is appropriate in the treatment of the short stature, delayed puberty and psychosocial problems associated with this condition. Early studies documented an adverse effect of high-dose androgens on final stature (10, l l ) , but most recent reports suggest no compromise of final adult stature (12-15). One reason for these conflicting results may be that earlier studies tended to use longer courses of high-dose androgen therapy, while recent studies have used shorter courses and lower doses (16). In a recent study of oxandrolone therapy in boys with constitutional delay of growth and puberty, the growth rate was significantly greater in the treatment group (8.6 cm/year), than in the control group (5.2 cm/year) (17); as the control group was also subsequently treated with oxandrolone, no conclusions regarding final stature could be drawn. Although no compromise of adult stature has been reported with androgen therapy at lower doses, these studies compared final height with initial height predictions, and did not evaluate placebo and treatment groups until a final adult stature was achieved. Thus, until a long-term, prospective, controlled trial is completed, it will not be possible to determine whether final stature benefits slightly from untreated pubertal delay. Most studies of growth in primary gonadal failure have focused on Turner’s syndrome because of its association with significant short stature. If the growth failure in this syndrome were totally due to the absence of gonadarche and the pubertal growth spurt, normal intrauterine and prepubertal growth would be expected, and the growth pattern should be analogous to that observed in hypogonadotropic hypogonadism. However, a comprehensive

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study of growth patterns in 150 untreated girls with Turner’s syndrome revealed that intrauterine growth is retarded, postnatal growth is normal until a bone age of 2 years, linear growth is stunted when the bone age is 2-1 1 years, and only slightly decreased after a bone age of 1 1 years (18). Thus, short stature in Turner’s syndrome is unlikely to be solely due to the absence of a pubertal growth spurt, but whether it is secondary to end-organ resistance to the effects of growth hormone (GH) or due to some other factor associated with the karyotype abnormality is still unknown. Although most girls with Turner’s syndrome have normal GH responses to provocative stimuli, the GH pulse amplitude and frequency are decreased compared to normal girls (19), and several cases of GH deficiency (GHD) have been documented (20-23). The effects of primary gonadal failure on growth are best seen in patients with only gonadal abnormalities or sex steroid resistant states. A study of a heterogeneous group of 18 agonadal patients with normal sex chromosomes prior to the institution of sex steroid therapy showed that prepubertal growth velocity in all patients was within the normal range for chronological age (3). Not all the subjects have been followed to final adult height. TIMING OF THE PUBERTAL GROWTH SPURT AND FINAL ADULT HEIGHT Although final adult stature is not adversely affected by delayed or absent puberty, it is affected by premature elevations in sex steroids of either adrenal or ovarian origin. A number of studies of children with congenital adrenal hyperplasia have reported compromised final adult stature in untreated or poorly treated patients. The effect of adrenal androgen suppression caused by glucocorticoid treatment on final adult height is more controversial. Klingensmith et al. reported that the final adult height of girls treated before the age of 1 year was 157.4 cm compared to 150.9 cm in untreated patients (24), and another study reported improved final height in patients who were adequately controlled (25). In contrast, Urban et a/. and DiMartino-Nardi et al. found no beneficial improvement in stature with early or aggressive treatment (26, 27); however, in many well-controlled patients who attained disappointing final adult heights treatment was initiated at bone ages above 10 years. Compromised final adult height in congenital adrenal hyperplasia may be due to premature epiphyseal fusion associated with elevated adrenal androgens and secondary to the suppressive effects of glucocorticoid therapy on growth. Thus, both overtreatment and undertreatment of the disorder may result in adult short stature. Children with precocious puberty of either central or peripheral aetiology experience a pubertal growth spurt comparable in magnitude to the normal pubertal spurt, but at an inappropriately early chronological age. The most comprehensive study of final height in untreated children with precocious puberty comprised a heterogeneous group in terms of aetiology, but all the children had premature development of secondary sexual characteristics and an early pubertal growth spurt with premature epiphyseal fusion (28). The final adult height in 27 girls with idiopathic precocious puberty was below 160 cm, except for one girl who had pubertal onset at age 7 years and reached an adult height greater than 170 cm. The authors comment that ‘short stature had been the most common complaint among older children and adults who have had idiopathic precocious puberty . . . in general, the younger the patient at the time of the onset of puberty, the shorter the adult height’ (28). If the short stature associated with precocious puberty is secondary to premature elevations in sex steroid levels, the rapid acceleration of skeletal maturation and early epiphyseal fusion, what would be the effect of suppression of gonadal sex steroids on linear growth and final adult height? Treatment of central precocious puberty with long-acting gonadotrophin releasing hormone (GnRH) analogues (GnRHa) results in gonadotrophin and sex steroid suppression, and a decrease in the rapid linear growth and rate of skeletal maturation (29). In 27 children with central precocious puberty GnRHa therapy resulted in a decrease in linear growth rate from 11 cm/year before therapy to 3.7 cm/year after 4 years of treatment (30). After 6 years of GnRHa therapy, the ratio of advancement in bone age to advancement in chronological age declined from 2.7 to 0.5 (31) and, in 10 children, predicted final height was increased by 18 cm compared to pretreatment evaluation. However, as most of the children who received long-term therapy have yet to achieve final adult stature and a prospective control group has not been evaluated, it is still not known whether suppression of gonadal steroids results in improved final height in precocious puberty.

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If suppression of gonadotrophins and sex steroids in children with precocious puberty improves predicted height, what would be the effect on final stature of a delay in the timing of normal puberty in short, but otherwise normal children? In a study of five pubertal children with GHD and two children with constitutional short stature, 0.5-1.3 years of GnRHa (buserelin) therapy did not improve predicted final height during the short study period (mean 0.84 years) (32). Controlled long-term studies are currently underway to determine whether longer periods of sex steroid suppression have any effect on final height in pubertal short, but otherwise normal, children. If early puberty is associated with decreased stature and a delay in the timing of puberty is associated with increased stature, what would be the effect of induction of puberty on extreme tall stature? Numerous studies have evaluated the efficacy of high-dose oestrogen treatment in girls with excessive tall stature (33-37) and in most cases the impact on final height predictions was assessed. These studies generally concluded that oestrogen treatment results in a decrease of 3.5-7.3 cm in final height (38), regardless of the precise treatment regimen or the method of comparison used. Similar results have been obtained with testosterone in boys with excessive tall stature (39). HORMONAL FACTORS IN THE PUBERTAL GROWTH SPURT Individuals with androgen-resistant states (i.e. testicular feminization) have a male genotype (XU karyotype) and a female phenotype, and have normal to increased levels of testosterone and oestradiol. This condition is ideal for studying the relative impact of adrenal or gonadal sex steroids on final adult height compared to contributions from Y-linked gene functions. In one study of 48 XY individuals with testicular feminization, final adult height was assessed as tall by normal female standards and similar to normal male standards (40). Another group study comprised 8 individuals with androgen insensitivity, who had normal male karyotypes, normal adrenal androgen levels and normal to high oestrogen and testosterone levels (41). In 5 subjects, final adult height was 1.4 SD of normal adult female height and -0.6 SD of normal adult male height. A spontaneous pubertal growth spurt of peak magnitude 7.4 cm/year occurred at a mean chronological age of 12.4 years. The timing and magnitude of the growth spurt resembled the female pattern more than the normal male pattern. These data suggest that oestrogen alone, derived primarily from aromatization of testicular testosterone and in the absence of adrenal or gonadal androgens, can stimulate pubertal growth which resembles the normal female spurt in timing and magnitude. However, as individuals with androgen resistance achieve a final height above that of normal females, factors derived from Y-linked genes must also make a contribution to stature. The taller stature of males may be a function of both the Y-linked genes and the later onset of the pubertal growth spurt. Early studies on the influence of sex steroids on GH secretion during normal puberty gave conflicting conclusions. Several authors found increased GH release in response to pharmacological stimuli such as arginine HCI, L-dopa and insulin, in pubertal compared with prepubertal children (42, 43). Short-term administration of sex steroids prior to provocative GH testing also increased GH secretion (44-46). Increased sex steroid levels are generally associated with increased endogenous GH secretion measured by methods such as continuous withdrawal or frequent day and night sampling (47-49). In a recent study of 21 children with idiopathic short stature, mean 24-hour GH concentrations were greater in children who received sex steroids (5.4 f 0.8 ng/ml than in those who did not (3.6 f 0.5 ng/ml) (50). Insulin-like growth factor I (IGF-I) levels rise throughout childhood with a dramatic increase at the time of puberty (51-53). The pubertal increase in IGF-I levels may be due to a direct effect of sex steroids on IGF-I production or an indirect effect mediated through increased GH secretion. During normal puberty, IGF-I levels correlate closely with plasma levels of sex hormones (53). Administration of sex steroids to functionally agonadal, GHintact (normal) children results in increased IGF-I levels (54). IGF-I levels can be correlated with growth velocity during the early phases of the pubertal growth spurt (55), but in late puberty, when growth velocity is decelerating, IGF-I levels remain high and do not correlate with growth velocity. Furthermore, there is little correlation between IGF-I levels and linear growth rate in GH-deficient children receiving GH therapy (56, 57). Other data suggest that sex steroids either have no effect or have an inhibitory effect on IGF-I, and oestradiol has even been used as adjuvant therapy in acromegaly (58-60).

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These conflicting results can be explained by a sex steroid dose effect. The following hypothesis is consistent with concepts suggested by Rosenfield et al. and Cutler et al.: in low doses, sex steroids act initially to stimulate GH secretion directly without significant effect on IGF-I (4, 45); in modest doses that result in circulating levels comparable to those observed in early endogenous puberty, the increase in GH secretion leads to an increase in circulating IGF-I; in high doses, oestradiol suppresses IGF-I (59, 60). It seems likely that sex steroids induce these changes in IGF-I at the level of GH, or even at higher hypothalamic or cortical levels. Further support for this hypothesis can be derived from a study by Parker et al. in which administration of testosterone to GH-deficient boys was not associated with an increase in IGF-I levels, while similar therapy in GH-sufficient children resulted in increased circulating IGF-I (61). The influence of sex steroids on GH secretion is best studied in those pathological conditions in which sex steroid secretion is abnormal or the GH axis is abnormal. Illig and Prader evaluated the GH response to provocative stimuli in 4 patients with anorchia and showed a significant increase in GH levels following testosterone therapy (62). In Turner’s syndrome, decreased levels of GH secretion and IGF-I are seen, which are increased by oestrogen therapy (19-23, 63). In children with constitutional delay of growth and puberty, a reduced GH response to provocative stimuli, which increased significantly after the onset of puberty, has also been reported (64). GH secretory dynamics have also been studied in precocious puberty. IGF-I levels are increased for chronological age, but are appropriate for pubertal stage (65). Spontaneous GH secretion in children with precocious puberty is increased compared to normal, age-matched, prepubertal children (66). However, in children who are afflicted both with GHD and with precocious puberty, IGF-I levels do not rise to levels appropriate for pubertal status (67). The interaction between sex steroids and GH can also be evaluated by studying disorders of the GH axis. In children with isolated GHD, puberty begins at a delayed chronological age, but at a bone age comparable to that seen in normal children, and progresses normally (68, 69). If, however, these children are not treated, final adult height is likely to be 6 SD below expected height (70). Thus, even if the pubertal growth spurt is qualitatively normal, final height is compromised in GHD. A recent study compared final adult height in 108 patients with GHD who had spontaneous pubertal onset (mean age 14.5 years in boys, 13.1 years in girls) with that of children with delayed onset of puberty (mean age 19.5 years in boys, 18.6 years in girls) (71). Final adult stature was significantly greater in children with delayed onset of puberty than in those with spontaneous onset. Furthermore, in a subgroup of patients with early pubertal onset, sex steroid suppression therapy with cyproterone acetate and/or medroxyprogesterone acetate resulted in improved final adult height compared to those in whom puberty was left to progress spontaneously.

CONCLUSIONS The mechanisms by which the adrenal and gonadal sex steroids induce the accelerated growth of the normal pubertal growth spurt have not been completely elucidated, but it is clear that they have a greater role in accelerating skeletal maturation than in direct stimulation of growth at the level of bone and cartilage. The sex steroids indirectly stimulate linear growth by increasing endogenous GH secretion. This, in turn, leads to increased circulating and tissue levels of IGF-I, which activate growth at the level of bone and cartilage. The long-term effects of sex steroids are probably biphasic, with low-to-moderate doses increasing linear growth and high doses exerting a greater influence on skeletal maturation, leading to compromised final adult height. In the absence of pubertal sex steroids, the increased growth velocity and skeletal maturation associated with the pubertal growth spurt does not occur. However, because of the lack of epiphyseal fusion, extended prepubertal growth continues and final adult height is not compromised. Premature production of pubertal sex steroids, however, leads to an early pubertal growth spurt and accelerated skeletal maturation, and results in compromised final adult height. Deficiencies in the GH axis (i.e. abnormal levels of GH releasing hormone, GH, or IGF-I) usually result in a late, though qualitatively normal, pubertal growth spurt, but do result in a compromised final adult stature.

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60. Clemmons DR, Underwood LE, Ridgeway RC, Kliman B, Kjellberg RN, Van Wyk JJ. Estradiol treatment of acromegaly: reduction in immunoreactive somatomedin-C and improvement in metabolic status. J Clin Endocrinol Metab 1980; 69: 571-5. 61. Parker MW, Johanson AJ,Rogol AD, Kaiser DL, Blizzard RM. Effect of testosterone on somatomedin-C concentrations in prepubertal boys. J Clin Endocrinol Metab 1984; 58: 87-90. 62. Illig R, Prader A. Effect of testosterone on growth hormone secretion in patients with anorchia and delayed puberty. J Clin Endocrinol 1970; 30: 615-18. 63. Cuttler L, Van Vliet G, Conte FA, Kaplan SL, Grumbach MM. Somatomedin-C levels in children and adolescents with gonadal dysgenesis: differences from age-matched normal females and effect of chronic estrogen replacement therapy. J Clin Endocrinol Metab 1985; 60: 1087-92. 64.Gourmelen M, Pham-Huu-Trung MT, Girard F. Transient partial hGH deficiency in prepubertal children with delay of growth. Pediatr Res 1979; 13: 221-4. 65. Pescovitz OH, Rosenfeld RG, Hintz RL et al. The role of somatomedin C and sex steroids in the accelerated growth of precocious puberty. J Pediatr 1985; 107: 20-5. 66. Ross JL, Pescovitz OH, Barnes K, Loriaux DL, Cutler GB Jr. Growth hormone secretory dynamics in children with precocious puberty. J Pediatr 1987; 111): 369-72. 67. Cara JF, Burstein S, Cuttler L, Moll GW, Rosenfield RL. Growth hormone deficiency impedes the rise in plasma insulin-like growth factor I levels associated with precocious puberty. J Pediatr 1989; 115: 64-8. 68. Tanner JM, Whitehouse RH. A note on the bone age at which patients with true isolated growth hormone deficiency enter puberty. J Clin Endocrinol Metab 1975; 41: 788-90. 69. Burns EC, Tanner JM, Preece MA, Cameron N. Final height and pubertal development in 55 children with idiopathic growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr 1981; 137: 155-64. 70. Rimoin DL, Merimee TJ, Rabinowitz D, McKusick VA. Genetic aspects of clinical endocrinology. Rec Prog Horm Res 1968; 24: 365-437. 71. Hibi I, Tanaka T, Tanae A et al. The influence of gonadal function and the effect of gonadal suppression treatment on final height in growth hormone (GH)-treated GH-deficient children. J Clin Endocrinol Metab 1989; 69: 221. (O.H.P.) Indiana University Medical Center James Whitcomb Riley Hospital for Children A539 702 Barnhill Drive Indianapolis IN 46223 USA

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Acta PEdiatr Scand [Suppl] 367: 119-125, 1990 REVIEW PAPER The Endocrinology of the Pubertal Growth Spurt O.H. PESCOVITZ From the Indiana University...
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