Clock time

FIGURE 5-6 Effects of age, stature, and growth rate on 24-hour serum GH profiles.

These observations tend to relate to long-term growth, over a period of 1 year usually, with GH secretion on a particular day. More detailed studies using repeated estimations of GH secretion in urine have linked GH secretion not only to growth rate but also to the intraindividual variation in growth rate that occurs on a week-by-week basis.

Considerable interest has centered on the components of the GH profile that contribute to the effect on growth. Early studies demonstrated that the growth process was pulse amplitude modulated and that GH pulse frequency did not change, remaining relatively fixed at a 200-minute periodicity. Changes in pulse frequency are largely confined to pathophysiological states, such as poorly controlled diabetes mellitus. Paradoxically, poor growth in chronic renal failure is associated with high GH secretion or at least high GH levels in the circulation, which in part

figure 5-7 Asymptotic relation between height velocity expressed as a standard deviation score (SDS) and the sum of GH pulses secreted over a 24-hour period.

may result from reduced GH clearance, although a degree of GH hypersecretion probably exists as well.

The pulse amplitude is determined predominately by the rate of entry of GH to the circulation. As the duration of the pulse is relatively fixed, the rate of change of GH in the circulation then becomes an important factor. Several studies suggested that the rate of rise of the pulse is the actual growth signal, so that the main information is actually contained in the rate of change of hormone concentration rather than in the actual level achieved. This rather presupposes that there is an actual level above which growth is likely to take place and that any further modulation is due to the rate of rise of the hormone secreted. This has not been tested formally but remains an intriguing possibility. The suggestion is not too far-fetched and it appears to be borne out to a certain extent by receptor studies. Rapid receptor turnover would be a prerequisite in pulsatile systems, and this is certainly the case with the insulin receptor in fat and muscle. Fairly rapid internalization takes place with the GH receptor, and the intracellular signaling system functions optimally with a 3-hour change in ambient GH concentrations.

One further component of the profile that appears to be important: the trough concentration of GH achieved in a secretory profile. Mention has already been made of the importance of the secretory pattern in rodents and to an extent in humans on influencing the generation of IGF-1 and for the maintenance of body composition. The precise role of trough concentrations in altering, or rather influencing, growth rate in humans is still far from clear. However, evidence suggests that, although the predominant effect on growth is determined by the amplitude of the GH secretory pulses, the effect of this pulse is modulated to a certain extent by the level of trough concentration. In the situation where the GH pulse amplitude is sufficient to generate normal growth, alterations in trough concentration appear to affect but little the overall growth rate. In the situation where GH secretion is attenuated due to a low GH pulse amplitude with consequent reduction in growth rate, the presence or absence of trough levels of GH has a profound effect on the growth rate observed. A situation of low GH pulse amplitude combined with a high trough concentration is associated with an extremely poor growth rate, compared to that observed with a similar GH pulse amplitude and a lower or normal trough concentration. These effects on growth rate are mirrored in the levels of serum IGF-1 concentration measured (Table 5-2).

Surprisingly little is known about the effect of alterations in GH receptor status and its effects on growth in normal individuals. Apart from the situation of GH receptor deficiency due to genetic abnormalities in the GH receptor gene, little is understood about differences in sensitivity to GH between individuals. This is a rather surprising situation, given that GH has been used for the treatment of a number of growth disorders over many years. The syndrome of GH resistance due to abnormalities in the GH receptor leads to an individual who produces considerable quantities of GH but very small amounts of IGF-1 or the other GH independent protein, IGF binding protein 3. The net result is a growth phenotype similar to but table 5-2 Growth Rate and IGF-1 Levels in 50 Children with Respect to Peak and Trough GH Concentrations (data shown as mean value)

GH Peak <50th GH Peak >50th Total

Height Velocity Standard Deviation Score

Total -1.70 -0.77 Serum IGF-1 Concentrations (U/1)

Total 0.31 0.49

probably more severe than individuals with GH gene deletion. The treatment of these individuals with IGF-1 is only partially successful, probably because GH is also required in its own right in the commitment of stem cells to the proliferative and hypertrophic zones of the cartilage. What happens during IGF-1 treatment is that any endogenous GH is suppressed, hence any chance of stem cells entering the proliferative zone is reduced and the effect of IGF-1 is simply to proliferate those cells available and gradually reducing in number during the course of therapy.

A few studies have suggested difference in GH sensitivity in the general population, but the lack of good dose response curves to adequately define the terms has seriously hampered the development of concepts in this area.

As suggested, the GH axis acts as a final common pathway in childhood for a number of pathophysiological situations affecting growth. In acquired hypothy-roidism, there is a general permissive effect of thyroid hormone on the whole growth axis. In hypothyroidism, there is a reduction of the efficacy of GHRH-stimulated GH release, probably as a result of a reduction in the transcription of the GH gene. Any GH secreted has probably less of an effect on the target tissues, as quite good evidence suggests that thyroxine is particularly important for mediating GH action at target tissue level. This is in addition to the effect of post-GH receptor of thy-roxine on cartilage growth.

Although GH plays an important role in prepubertal growth, there is probably an interaction with other factors. The juvenile or mid-growth spurt is a good example of this. If an individual's growth chart is examined, an increase in growth rate can be detected around 6-8 years old. The precise etiology of the spurt is unclear, but it is likely that adrenal androgens, which are increasing in circulatory concentration at this time, play a role. Supportive evidence comes from patients with early onset Addison's disease, where adrenal function is lost. Patients with this disease do not manifest a mid-childhood growth spurt, or at least it is attenuated. Of interest is the observation that these patients and indeed anyone who has suppressed adrenal androgen secretion have delay in the timing of the onset of puberty. This suggests that adrenal androgen production is involved not only in the mid-childhood growth spurt but also in priming the hypothalamopituitary axis for puberty.

endocrinology of puberty

The pubertal growth spurt in human subjects represents the contribution of sex steroids and GH each contributing 50% of the height gained. Augmentation of GH secretion occurs during puberty with an approximate two- to threefold increase in amplitude of the secretory bursts, whereas the frequency of GH pulses does not change. Many cross-sectional studies demonstrated that the increase in GH pulse amplitude coincides with the pubertal growth spurt and confirmation of this observation has come from detailed longitudinal studies where puberty has been induced with the hypothalamic peptide gonadotropin-releasing hormone (Figure 5-8).

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