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1 2 3 4 5 Pubertal stage figure 5-8 Changes in GH production during a 24-hour period in females (closed circles) and males (closed squares) at different stages of pubertal development.

Sex steroids play an important role in regulating the physiology of GH secretion in childhood. Estrogen has long been known to alter GH responses to stimuli and small doses of estrogen, when given to girls with gonadal dysgenesis, enhance GH secretion, as does testosterone administration to boys with delayed puberty. Conversely, suppressing puberty, as in the situation of precocious puberty, with a gonadotropin-releasing hormone analogue leads to a decrease in GH secretion. Both testosterone and estradiol stimulate GH, so the question arises as to whether they act as independent agents. Nonaromatizable androgens such as oxan-drolone do not greatly effect GH secretion. The effect of testosterone is certainly time and probably dose dependent. Androgen receptor blockade has little effect on GH secretion, while the antiestrogen tamoxifen blocks testosterone stimulation of GH secretion, suggesting that aromatization of testosterone to estradiol, which then acts via the estrogen receptor, may be more important for testosterone effects on GH.

The precise mechanisms by which the sex steroids alter the interaction of GHRH and SS in the generation of GH pulses in childhood is unclear. However, a large amount of experimental data, primarily from the rat, suggests that neonatal exposure to steroids has an imprinting effect on the hypothalamic systems regulating

GHRH and SS, but their full expression of this requires continued gonadal steroid exposure in adult life. Prepubertal gonadectomy can markedly alter the expression of the sexually dimorphic GH secretory pattern in the adult rat. In addition to the hypothalamic effects, the raised basal GH release by estradiol in normal rats may be due to effects directly on pituitary GH synthesis or GH cell number.

Estrogen has additional effects on the growth process. The dose-response effect between estrogen and growth is biphasic in nature, with a peak acceleration in growth observed with ethinyl estradiol doses of approximately 10 |g per day, which is equivalent to the midpoint of pubertal development. Increasing the estrogen dose leads to a reduction in growth rate and an advance in skeletal maturation. It would appear that estrogen has two effects in puberty. The first is to augment GH secretion in lower doses, leading to generation of the pubertal growth spurt and, at higher doses, certainly in the rat, to suppression or at least reduction in GH release; the second is to accelerate ossification and closure of the growth plate. This latter process appears to depend highly on the density of estrogen receptors in the growth plate. In experiments of nature where estrogen is either deficient due to aromati-zation defects or unable to act due to estrogen receptor mutation, growth continues, albeit slowly, and the epiphyses do not close.

gh secretory patterns in adulthood

Serum GH concentrations and pulsatile GH secretion fall in early adulthood by 25 or 50% of the values observed during puberty. This is a particularly interesting observation in view of the fact that the concentrations of sex steroids, which are associated with the increase in GH secretion, have changed but little during the latter part of puberty. As suggested already, the overall suppressing effect might arise as a result of the biphasic action of estrogen on GH secretion, but evidence to support this suggestion is lacking in the literature. The aging process itself may well have an important effect on the number and size of the somatotropes in the pituitary and also on GH gene expression, both decreasing with age. Clinical studies with GHRH-stimulated GH release support the concept of a decreasing GH releasable pool with age, as do exercise studies.

It is probably also worth mentioning the studies conducted in adulthood, which probably pertain to the endocrinology of growth in childhood. Gender, body composition, and exercise play important roles in determining circulating GH concentrations. The sexual dimorphic patterns of GH secretion in humans are discussed earlier in this chapter. The gender effect is certainly less marked than in the rodent but clear differences between males and females can be demonstrated. Gender is also a strong modifier of the negative impact of age. The major change of GH secretion with age is the diminution in GH pulse amplitude, and the presence of sex steroids would seem to be important, since women at premenopausal age with normal levels of estrogen are relatively protected from the negative effects of increasing age. This effect is not seen in the postmenopausal age group. There is, in addition, a further interaction between gender and the effects of both adiposity and GH secretion.

conclusion

The human growth process can be broken down into at least three distinct phases of growth: infancy, childhood, and puberty. Further subdivisions probably could be made, but at least these three phases are regulated by different aspects of the endocrine system. Very little is known about antenatal growth and growth in the first year of life. The information available, however, strongly suggests that growth in utero and probably in the first 6 months of life is largely GH independent. The precise factor(s) that determine this growth process are still unclear. The nutritional status of the individual is clearly an important determinant, but the precise factors that translate nutrient input into growth remain to be defined. Transgenic technology coupled with knockout studies strongly suggest that the IGF axis plays an important role in this process. During the first year of life, there is a gradual switch from this nutritionally dependent growth process to GH dependency. Full dependence on GH for the growth process appears to be attained toward the second year of life, and thereafter the majority of childhood growth can be explained in terms of the amount of GH secreted by the individual. GH appears to be the final common pathway for integrating the effects of a number of growth signals, and in patho-physiological situations where growth is affected, abnormality in the GH axis can be expected. The pubertal growth spurt is made up by a contribution of sex steroids coupled with GH. The most important component appears to be estrogen in females and the aromatization of testosterone to estrogen in males.

suggested reading

Brook CGD (ed). Clinical Paediatric Endocrinology, 3rd ed. Oxford: Blackwell Scientific Publications, 1995.

Robinson ICAF, Hindmarsh PC. The growth hormone secretory pattern and statural growth In: Kostyo JL (ed). Handbook of Physiology, Section 7. The Endocrine System. Vol. 5. Hormonal Control of Growth. New York: Oxford University Press, 1999:329-395.

Ulijaszek SJ, Johnston FE, Preece MA. The Cambridge Encyclopedia of Human Growth and Development. Cambridge: Cambridge University Press, 1998:182-184.

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