The Role of Sex Steroids in Controlling Pubertal Growth

R. J. Perry; C. Farquharson; S. F. Ahmed

Disclosures

Clin Endocrinol. 2008;68(1):4-15. 

In This Article

Local Effects of Sex Steroids on the Growth Plate

In addition to its systemic effects GH also has a direct action at the level of the growth plate. GH enhances the recruitment of resting zone chondrocytes and local IGF-I production in the growth plate.[25,26,27,28] It remains unclear about the contribution of systemic vs. local IGF-I to longitudinal growth. However, they both appear to have an impact on longitudinal growth (in mice at least). The liver-derived IGF-I gene-deleted mouse model (LID) has normal growth but circulating IGF-I levels are only reduced by 75%. When the LID mice were crossed with the acid labile subunit (ALS) gene-deleted mice (ALSKO), the LID/ALSKO mice had a further reduction in circulating IGF-I levels (85-90%) and showed early postnatal growth retardation.[29] But tissue IGF-I may still play a role because the total IGF-I knockout mice show more marked growth retardation. However, basal IGF-I production by growth plate chondrocytes is reported to be minimal.[30,31]

Sex steroids are likely to have a direct action on chondrocytes because the AR and both ER-α and ER-ß, have been demonstrated in GP tissue at the mRNA and protein level in several species, including rat, rabbit and human.[13]

The AR has been demonstrated in all layers of the human growth plate at different ages with no significant gender variation.[32,33,34,35] Several studies support a direct stimulatory effect of androgens on the growth plate cartilage. In vitro studies have shown that DHT regulates proliferation and differentiation of cultured human epiphyseal chondrocytes, probably by promoting local IGF-I synthesis and increasing IGF-I receptor expression.[36] The sex-specific response of rat costochondral growth zone chondrocytes to testosterone requires the further metabolism of the hormone to DHT and this DHT effect in the male growth plate is maturation-state dependent.[37]

Similarly in vivo, a nonspecific ER blocker (Faslodex, Zeneca Pharmaceutical Company, Wilmington, DE) did not prevent the advancement of bone maturation in mice treated with testosterone.[38] Also, direct injections of testosterone into the rat tibial epiphyseal growth plate increased growth plate width without alteration of IGF-I production.[39] Furthermore, DHT stimulates longitudinal bone growth in ovariectomized (OVX) rats[40] and testosterone increases growth plate width in castrated, hypophysectomized male rats.[41]

The ERs have been demonstrated in all maturational zones of the human growth plate during development and puberty. However, there is conflicting evidence from in vitro studies on the effect of oestrogen on chondrocyte proliferation and differentiation.[42,43,44,45,46,47,48,49] Some of the discrepancies may be explained by the demonstrated ability of chondrocytes to synthesize oestrogen themselves.[49,50,51] Activation of the ERs by locally produced oestrogen could minimize or eliminate the effect of exogenous oestrogen. To complicate matters further, oestrogen signalling can occur via genomic or nongenomic pathways. The new oestrogen receptor GPR30 is expressed in the human growth plate and down-regulated during pubertal progression.[52] This new receptor may explain some of the previous "non-genomic" actions of oestrogen. It is a G-protein coupled receptor which is also involved in changes in calcium levels.[53] Furthermore, some of the rapid responses to oestrogen, including activation of protein kinase C, are limited to cells from female animals.[46,54,55]In vivo, oestrogen inhibits chondrocyte cell division in the proliferative zone (PZ) of the rat growth plate.[56,57,58] The age-related decrease in size of the hypertrophic chondrocytes[59,60] is enhanced by oestrogen.[58] In rats, the withdrawal of oestrogen by OVX stimulates longitudinal bone growth.[61] This increase in bone length is associated with increased chondrocyte proliferation[51] growth plate width[51] and IGF-I production.[40,51] Similarly, in humans, tall girls treated with high-dose oestrogen display a rapid reduction in GV but have only a modest decrease in serum IGF-I suggesting a direct, non-GH-dependent, effect of oestrogen.[62] Moreover, children with precocious puberty (PP) and GH deficiency can have a pubertal growth spurt.[63]

Meta-analysis of longitudinal bone length in these knockouts has shown that the role played by the oestrogen receptors (ER) in association with bone length may depend on sex and age ( Table 1 and Table 2 ).[64,65,66,67,68,69,70,71,72,73,74,75,76,77] ER-ß has an inhibitory effect on longitudinal bone growth in adult female mice only.[65,66,70] It has been hypothesized that this inhibitory action is only seen in the presence of elevated serum oestrogen levels - this is supported by the finding that adult female BERKO (ER-ß knockout) mice have the highest serum oestrogen levels[71] during which period the inhibitory effect of ER-ß is exclusively seen. Furthermore, female ERKO (ER-α knockout) mice have shorter bones than female DERKO (both ER-α and ER-ß absent).[65,66] Both of these strains have markedly elevated serum oestrogen levels due to an inactive feedback loop.[65]

Knocking out ER-ß does not affect femur length in male mice of any age.[70,71,75] Finally, in the presence of high levels of oestrogen, ER-ß induces fusion of the growth plate in older female mice.[66,67] Knocking out ER-α does not have an effect on growth of younger mice but may inhibit growth in the older ones.[64,65,66,67,68,69,75,76] There is no evidence of sexual dimorphic effects. The patient lacking ER-α (hERKO) carries a mutation at residue 157 in the protein, which would allow the short, 46-kD spliced form of ER-α to be synthesized.[78] This is one possible explanation for discordance in phenotype between mice and man.

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