Growth Hormone and Growth Factors

GH secretion approximately doubles during puberty in boys and girls in the basal state or after stimulation but decreases after pubertal development. Remarkably, peak values after hexarelin, a 6–amino acid GH-releasing peptide (or GH secretagogue) stimulates as much GH secretion in prepuberty as in puberty. The greater elevation in girls starts at an earlier age and pubertal stage than in boys due to the earlier onset of puberty in girls. GH secretion increases coincident with the onset of breast development (Tanner stage 2) and is maximal at Tanner stage 3 to 4 breast development; in boys, GH rises later and peaks at stage 4 genital development. GH secretion and IGF-1 levels decrease after late puberty in both sexes. Adolescents of normal height have an inverse relationship between weight and GH levels. Increased GH pulse amplitude and content of GH secreted per pulse (not but frequency, metabolic clearance rate, or intersecretory burst interval and half-life of GH) in the basal state are mainly responsible for the augmented GH levels.283

The increase in estradiol at puberty, which in boys results from testicular secretion and extraglandular synthesis from testosteroneand androstenedione and in girls from secretion by the ovaries, is the principal mediator of the increase in pulse amplitude and amount of GH secreted per pulse. Administration of exogenous androgens in delayed puberty raises GH secretion. Transdermal application of testosterone increases spontaneous GH secretion overnight independent of growth hormone–releasing hormone (GHRH), because infusion of GnRH antagonist does not affect this phenomenon.284 The effect of testosterone is mediated mainly through its conversion to estradiol, because treatment of late pubertal boys with tamoxifen, an estrogen receptor blocker, causes smaller GH secretory peaks and fewer GH secretory episodes. Exogenous estrogen increases the peak GH reached after insulin-induced hypoglycemia, exercise, and arginine, a priming effect that is used in clinical practice, because estrogen administered before a provocative test in prepubertal subjects increases the GH response. Androgens that cannot be aromatized to estrogen (e.g., oxandrolone, dihydrotestosterone) have less effect on GH secretion; however, androgen blockade with flutamide increases GH secretion. Dihydrotestosterone, which is not aromatized to estrogen, does not increase GH secretion or the plasma concentration of IGF-1 and may decrease the integrated GH secretion, but it still stimulates increased growth rate, suggesting a possible direct effect of androgen on pubertal growth independent of GH or estradiol.269 Increased GH secretion also occurs in sexual precocity. GH secretion decreases with the fall in gonadal steroid levels after treatment of CPP with potent GnRH agonists.285

GH deficiency or GH resistance causes an attenuated pubertal growth spurt, indicating the importance of GH and IGF-1 in this process. Severe primary or secondary hypogonadism leads to a minimal or absent growth spurt, demonstrating the primary role of gonadal steroids in pubertal growth. Hypopituitary patients deficient in GH and gonadotropins do not have an adolescent growth spurt when GH alone is replaced; gonadal steroids must also be given, substantiating the interaction of GH and gonadal steroids in the pubertal growth spurt. In normal puberty, neither the magnitude of the increase in GH secretion nor the concentration of plasma IGF-1 correlates with the PHV of the pubertal growth spurt. Although a threshold level of GH secretion is necessary, the extent of the growth spurt correlates with gonadal sex steroid secretion. Individuals with both CPP and GH deficiency (usually as a consequence of cranial irradiation for a brain tumor) have a growth spurt clinically indistinguishable from that of CPP and normal GH secretion.269 After treatment with a GnRH agonist for sexual precocity, growth velocityin patients with GH deficiency and CPP is decreased and pubertal progression is suppressed, illustrating the direct effect of gonadal steroids, principally estradiol, on the pubertal growth spurt.

Urinary GH excretion reflects serum levels and changes occurring with pubertal development. A peak is reached at pubertal stage 3 to 4. The level is higher in boys than in girls.

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