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

Systemic Effects of Sex Steroids on GH-IGF-I Axis

The striking increase in growth velocity (GV) during puberty is under complex endocrine control. GH increases growth at puberty through the stimulation of insulin-like growth factor-I (IGF-I) production. During puberty the pulsatile secretion of GH increases (1.5 to 3-fold) along with a greater than three-fold increase in serum IGF-I levels. Peak IGF-I levels occur at 14.5 years in girls and 1 year later in boys.[1] The rise in mean 24-h GH levels results from an increase in the maximal GH secretory rate and also in the mass of GH per secretory burst.[2,3] The increase in GH secretion during puberty shows a sexually dimorphic pattern that parallels the change in GV. In girls, an increase in circulating GH is seen relatively early in puberty at Tanner breast Stage 2 (B2) with peak levels coinciding with B3-4. In boys, this increase in GH is seen later with the peak occurring at Tanner genital Stage 4 (G4).[4] After secondary sexual development is complete, GH and IGF-I levels fall to prepubertal levels in both sexes. The secretion of GH is mediated by two hypothalamic hormones: growth hormone releasing hormone (GHRH) and somatostatin. GHRH has a stimulatory effect whereas somatostatin has an inhibitory effect. These hypothalamic influences are tightly regulated by an integrated system of neural, metabolic and hormonal factors.[5]

In animal studies (principally rodents) sex steroids influence GH synthesis and secretion with effects on both the hypothalamus and anterior pituitary. In the neonatal period, sex steroids influence the number of GHRH neurones which will be present in the adult hypothalamus and also their response to postpubertal steroids.[6] Postpubertally, androgens modify hypothalamic somatostatin synthesis whereas oestrogens modify GHRH synthesis. In addition, both neonatal and postpubertal steroids influence the secretory pulsatility of anterior pituitary hormone release by altering hypothalamic synaptic organization.[6] At the level of the pituitary, sex steroids modify the response of somatotrophs to somatostatin.[6]

Dihydrotestosterone (DHT) and oxandrolone increase GV in boys with delayed puberty without any alteration of serum GH/IGF-I.[7,8,9,10] In contrast, testosterone, typically, increases GV in association with an increase in GH/IGF-I.[11] This ability of testosterone to stimulate GH secretion is principally due to its conversion to oestrogen by aromatization. This is supported by a study in pubertal boys who showed a reduction in GH and IGF-I when treated with tamoxifen [an oestrogen receptor (ER) blocker].[12] The nonaromatizable androgens (DHT and oxandrolone) increase GV independent of GH/IGF-I suggesting that "pure androgens" may stimulate growth through other mechanisms, possibly via a direct action on the androgen receptor (AR) within the growth plate cartilage.[13]

Oestrogen stimulation of growth is largely dependent on pituitary GH and is mediated via the oestrogen receptors, oestrogen receptor-alpha (ER-α) and oestrogen receptor-beta (ER-ß), which are expressed in the anterior pituitary as well as the hypothalamus. GH and oestrogen levels show positive correlations in prepubertal girls and boys.[14,15] Endogenous oestrogen in peri-pubertal children increases GH sensitivity.[16] Oestrogen priming for GH-stimulation testing has been shown to augment GH release in normal adolescents.[17] Furthermore, GH secretion is reduced when oestrogen signalling is blocked.[12,18] This tight relationship between oestrogen and GH status is further demonstrated by the strong correlation between oestrogen and GH concentrations throughout normal female puberty.[19] GH levels are higher in women compared to in men.[20,21] As boys and girls with IGF-I deficiency (Laron syndrome) do not have a discernible pubertal growth spurt,[22] a major part of the stimulation of growth by oestrogen is through the GH-IGF-I axis. The effect of exogenous oestrogen depends on its form. If oestrogen treatment is administered orally (for hormone replacement therapy), large supraphysiological doses are required as oestrogen is actively metabolized by the hepatic cytochrome system. This supraphysiological concentration in the portal circulation perturbs many aspects of hepatic function. The liver is the major site of GH-regulated metabolism and the main source of IGF-I.[23] Oral oestrogen administration leads to increased circulating GH levels and a reduction in IGF-I production. The high oestrogen concentration in the portal circulation impairs hepatic IGF-I production and increases the concentrations of growth hormone binding protein (GHBP) which binds to GH and thereby blunts its action. There is also stimulation of the synthesis of angiotensinogen, clotting factors, lipoproteins and the binding proteins for several steroid hormones. These metabolic sequelae are not seen with transdermal administration.[24]


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