The Role of Sex Steroids in Controlling Pubertal Growth

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


Clin Endocrinol. 2008;68(1):4-15. 

In This Article

Delayed Sexual Maturation

This condition, often referred to as constitutional delay of growth and puberty (CDGP), typically affects boys. The clinical features include relative short stature for chronologic age, delayed puberty and delayed bone maturation in otherwise healthy adolescents. A relatively short upper body segment is common at presentation and persists at attainment of FH.[120] Although FH is predicted to be normal based on BA estimation, adolescents with CDGP are usually shorter than their mid-parental height.[120,121,122,123] There is often a family history of delayed puberty and a personal history of atopy.[124] The decrease in FH may be explained by the short stature at onset of puberty, shorter duration between onset of puberty and pubertal growth spurt and compromised peak GV.[125] A short course of testosterone enanthate or low doses of oxandrolone can accelerate the pubertal growth spurt without altering FH.[126,127] However, FH in boys with CDGP may be improved by treatment with aromatase inhibitors by delaying bone age progression.[128]

A delay in puberty can be seen in virtually any chronic disease of childhood.[129] Several factors influence the degree to which growth and pubertal development are affected. These include age, duration of illness and its severity, nutritional status and medications. This form of delayed puberty is often mistaken for CDGP but may be more profound and protracted depending on the underlying condition.

Hypogonadism can be classified according to the serum gonadotrophin levels; high levels indicate primary gonadal failure and low levels indicate disorders at the hypothalamo-pituitary level.

In hypogonadotrophic hypogonadism, such as Kallman's syndrome, puberty may be completely absent. The pubertal component of the ICP model will be lacking so childhood growth will continue at its slowly declining rate. In untreated individuals growth will continue until the third decade and FH may actually be taller than average due to this persistence of the childhood component of growth. However, this results in abnormal body proportions with a relatively longer lower body segment. Short stature may be seen initially relative to chronologic age but a normal FH is achieved after sex steroid replacement.[130]

This condition results from a primary defect of the gonads which renders them unresponsive to gonadotrophins. A similar growth pattern to those affected by hypogonadotrophic hypogonadism is observed. However, the commonest cause of primary hypogonadism in boys is Klinefelter syndrome (47,XXY) which is associated with tall stature. Often there is a normal onset of puberty but pubertal arrest can occur at any stage. If spontaneous puberty does occur then the magnitude and timing of pubertal growth is reported to be normal, with a mean FH of 186 cm. The tall stature may be attributable to the extra sex chromosome. Although testes are of normal size and consistency at birth, they fail to grow normally during puberty and seldom exceed 4 mls. Testicular involution followed by androgen deficiency then frequently occurs. Salivary testosterone levels are significantly lower by 16 years of age.[131]

In boys with prenatal testicular atrophy (e.g. "the vanishing testes") the childhood component of growth is reported to be normal.

In girls with Turner syndrome, the commonest form of ovarian dysgenesis, the growth pattern is influenced by the skeletal problems (haploinsufficiency of SHOX) and the absence of oestrogens during adolescence. They usually demonstrate mild growth retardation in utero followed by slow growth during infancy with a delayed onset of the childhood component of growth and then slow growth during childhood. If the ovaries completely lack follicles the previous deterioration of growth rate will be further attenuated in puberty, due to absence of a growth spurt.

Delayed puberty is often seen in patients with GH deficiency or a GH receptor defect. A common feature to both these conditions is low or lack of IGF-I function. This highlights the possible role of IGF-I in the regulation of puberty.[132,133]

In type 1 diabetes mellitus (T1DM), pubertal delay has also been described. However, this was not confirmed in more recent studies where FH was unaffected. Nonetheless, the pubertal growth spurt in T1DM may be attenuated.[134] Primary hypothyroidism can also be associated with hypogonadotrophic hypogonadism which is reversible with thyroxine treatment.[135] Men with primary hypothyroidism have a subnormal LH response to GnRH but normal response to hCG. Their low free testosterone levels normalize after thyroxine treatment due to changes in SHBG concentrations.[135] Although children with primary hypothyroidism may continue to grow for a longer period after therapy is initiated, FH can still be restricted.[136] Cushing's disease is associated with a delayed onset or mid-pubertal arrest of puberty which is reversible after removal of the source.[137,138] GH deficiency is common following treatment of childhood onset Cushing's disease and may persist for many years.[139] Early investigation for diagnosis and treatment of GH deficiency is thus advocated.[140] FH within target range can be achieved but excess adiposity remains a potential long-term complication.[140]

Some conditions have already been discussed under the "hypergonadotrophic hypogonadism" section. Boys with mixed gonadal dysgenesis (45,X/46,XY) demonstrate short stature during childhood. This relates to the 45,X cell line and not the androgen deficiency. The severity of the short stature depends on the degree of mosaicism in a similar fashion to girls with Turner syndrome. Other abnormalities of the sex chromosomes in girls include 46,XY pure gonadal dysgenesis, 47,XXX and androgen insensitivity syndrome. Besides being influenced by abnormal sex hormone production or sensitivity in puberty; their growth may also be influenced by other growth-enhancing genes (of unknown nature) of the X- and Y-chromosomes. The Y-chromosomes as well as the supernumerary X-chromosomes in males may be associated with tall stature.

Boys with 47,XYY are of normal size at birth but show an increase in GV from 2 years of age. At the time of pubertal onset the average 47,XYY boy is 7.6 cm taller than controls. The pubertal growth spurt is also larger and of longer duration resulting in a FH of 188 cm.[131] Girls with extra X-chromosomes do not generally have tall stature.[141,142] Girls who are 47,XXX have a reduced size at birth but demonstrate an increase in GV during mid childhood, akin to 47,XXY boys, owing to greater leg length. Pubertal growth spurt is reported to be of normal magnitude but occurs 6 months later than that of controls and their FH is normal.

46,XY girls with CAIS achieve a FH in between that of normal men and women.[89,143,144] Individuals with CAIS and intact gonads have a normal female pubertal growth spurt despite the lack of androgen action.[89] The FH of published cases of XX gonadal dysgenesis (XXGD) and XY gonadal dysgenesis (XYGD) were compared by Ogata et al.[145] The mean FH of XYGD patients was significantly greater than that of XXGD patients.[145] This lends support to the existence of Y-specific growth genes that promote statural growth independently of the effects of sex steroids.[146] The childhood component of growth is unaffected by early gonadectomy emphasizing the relative lack of importance of sex steroids in the prepubertal phase of normal growth.[147]

In summary, there is ample evidence to suggest that sex steroids, particularly, oestrogen play a vital role in modulating linear growth through the systemic GH-IGF-I axis, as well as, at the level of the growth plate. Clinical disorders of sex steroid synthesis and action lead to an abnormal pattern of growth. An improved understanding of this effect of sex steroids on growth requires a combination of clinical and basic experimental studies.

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