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

Disorders of Puberty that Lead to Growth Disturbance

This is traditionally defined by the onset of puberty before the age of 8 years in girls or 9 years in boys. The occurrence of menarche before the age of 10 years also indicates sexual precocity. In the USA, these criteria have been reconsidered due to a community-based study of 17 000 girls who showed a trend towards earlier breast development.[99] However, age at menarche is unaltered, suggesting that the tempo of puberty in the early developers may be slower. It has been proposed that the age of 7 years for white girls and 6.5 years for the African American population should be used as a cut-off for defining early puberty.[100] In boys, the cut-off is unchanged. In Europe, the original criteria are still valid as there is no evidence of a recent reduction in age at onset of puberty in either gender.[101] Precocious puberty can be classified as central precocious puberty (CPP) or gonadotrophin-independent precocious puberty (GIPP). CPP involves the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. In GIPP the presence of sex steroids is independent of pituitary gonadotrophin release.

Isolated premature thelarche (IPT) is a benign condition characterized by early breast development in girls, usually under the age of 2 years, in the absence of any other pubertal changes. This is a self-limiting condition[102] and FH is unaffected.[103] A variant condition, termed thelarche variant, exhibits features intermediate between IPT and CPP.[104,105] There appears to be a continuum between IPT and CPP; approximately 15% of girls with IPT may progress to CPP.[106] The thelarche variant may be associated with the development of pubic hair and detectable oestradiol but FSH levels predominate. However, they do show increased GV and advanced skeletal maturation[105] but FH appears be unchanged.[107]

This condition is defined as cyclical vaginal bleeding in prepubertal girls without any other signs of puberty. Gonadotrophins are not raised but an endometrial echo is visible on ultrasound during the bleeding phase. However, as the differential diagnosis includes child sexual abuse and vaginal malignancy, examination under anaesthesia may be required if the history and examination are not typical. Although poorly understood, it appears to be a benign and self-limiting condition with unaffected FH.[108]

In some individuals adrenarche (adrenal puberty occurring between 6 years and 8 years) is associated with sufficient androgen production to cause pubic hair development which may be referred to as exaggerated adrenarche. When symptoms occur at an earlier age this is termed premature adrenarche. Commonly associated symptoms include a history of body odour, greasy skin and hair, weight gain and some mood disturbance. At presentation, children may be taller and have an advanced BA. Although prepubertal growth in affected girls is enhanced with respect to normal controls, this enhancement may be compensated for by a decrease in the pubertal growth component leading to a FH within the target range.[109,110]

CPP has an incidence of 1 in 5000-10 000 children with a female to male ratio of greater than 20 : 1.[111] The spectrum of idiopathic CPP contains transient, alternating, slowly progressive and rapidly progressive forms.[112] Ninety-five per cent of girls with CPP have idiopathic CPP whereas over 50% of boys have an identifiable aetiology.[113] Acceleration of growth is almost invariable in CPP but these children will also show premature ossification and fusion of the growth cartilage and early cessation of growth. Girls who present before 6 years are reported to lose 12-15 cm in FH whereas those who present after 6 years lose 7-10 cm.[114] The risk of short stature is higher in children with associated GH insufficiency or limited potential to grow due to cranial or craniospinal irradiation. Early puberty may result in a greater sitting height to leg length ratio at FH as an indicator of the premature bone maturation. The interpretation of height gain from treatment in CPP patients should be judged cautiously as FH predictions are based on BA estimation, a technique based on reference data from normal healthy children.

GIPP is characterized by pubertal sex steroid levels with prepubertal or suppressed gonadotrophins. Excess secretion of the hormone leads to hypertrophy of the target tissue as well as acceleration of growth and bone maturation. The source of hormone production can be gonadal, adrenal (tumour or congenital adrenal hyperplasia, CAH), ectopic (gonadotrophin- or hCG-producing tumours) or exogenous. Additionally, the McCune-Albright syndrome produces discordant sexual development. This syndrome is characterized by irregular pigmented café-au-lait patches and polyostotic fibrous dysplasia. Pubertal signs are usually discordant with early bleeding in girls and no evidence of gonadotrophin cyclicity. In this condition, growth acceleration may also be due to hyperthyroidism or GH excess. It occurs due to a generalized mutation of part of the G protein in endocrine tissues leading to overactivity.

In males, testoxicosis or familial male PP can lead to pubertal changes and growth acceleration. The testes are often small for the degree of virilization.[115]

In all of these conditions the excess sex steroid production leads to advanced epiphyseal maturation which can predict the timing of the onset of central puberty as there is remarkable synchrony between the onset of central puberty and skeletal maturation across the various disorders of puberty.[116] Central puberty may occur due to exposure of the hypothalamus to high levels of sex steroids; this phenomenon is known as "priming".

Although puberty tends to be delayed in hypothyroid children, severe longstanding hypothyroidism may cause GIPP probably mediated by TSH stimulation of the FSH receptor.[117] Characteristically, there is testicular enlargement without significant virilization in boys and breast development, uterine bleeding and multicystic ovaries in girls. Thyroxine treatment can lead to resumption of the normal consonance of puberty and catch-up growth.[118] However, FH may be reduced attributable to a rapid advance in epiphyseal maturation.[119]

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