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The Role of Sex Steroids in Controlling Pubertal Growth

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The Role of Sex Steroids in Controlling Pubertal Growth


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


Clin Endocrinol. 2008;68(1):4-15. ?2008 Blackwell Publishing

Posted 03/03/2008


Summary and Introduction


Longitudinal growth, which is primarily due to chondrocytic activity at the level of the epiphyseal growth plate, is influenced by many hormones and growth factors in an endocrine and paracrine manner. Their influence is even more complex during the accelerated growth period of puberty that accounts for about 20% of final adult height. Although abnormalities of growth during puberty are very common, the underlying mechanisms that govern the beginning and cessation of pubertal growth at the level of the growth plate are poorly understood. Sex steroids play a crucial role in pubertal growth both at the systemic level via the GH/IGF-1 axis and at the local level of the epiphyseal growth plate. In both sexes it is now accepted that oestrogen is the critical hormone in controlling growth plate acceleration and fusion. This paper reviews the mechanisms that influence pubertal growth and the problems that are associated with disorders of gonadal function.



Longitudinal growth is a complex process regulated by several hormonal and genetic factors, environment and nutrition. Among these, sex steroids are of crucial importance and the most obvious demonstration of their effect on human growth is the initiation, maintenance and decline of the pubertal growth spurt. The effect of sex steroids on growth can be studied in detail at two levels: the systemic level and the local level of the epiphyseal growth plate. In this review, we summarize current knowledge about the mechanisms by which sex steroids influence growth before dealing specifically with the growth problems associated with gonadal disorders.


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.[7-10] 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-?), 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]


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.[25-28] 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

Sex steroids are likely to have a direct action on chondrocytes because the AR and both ER-α and ER-?, 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.[32-35] 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.[42-49] Some of the discrepancies may be explained by the demonstrated ability of chondrocytes to synthesize oestrogen themselves.[49-51] 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.[56-58] 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]


Lessons Learned from ER Knockouts in Mouse and Man

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 ).[64-77] ER-? 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-? knockout) mice have the highest serum oestrogen levels[71] during which period the inhibitory effect of ER-? is exclusively seen. Furthermore, female ERKO (ER-α knockout) mice have shorter bones than female DERKO (both ER-α and ER-? absent).[65,66] Both of these strains have markedly elevated serum oestrogen levels due to an inactive feedback loop.[65]


Knocking out ER-? does not affect femur length in male mice of any age.[70,71,75] Finally, in the presence of high levels of oestrogen, ER-? 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.[64-69,75,76] 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.


Growth in Puberty

There are at least three distinct phases of postnatal growth. The infantile phase is the first phase with rapid GV during foetal life followed by rapid deceleration up to 3 years of age. The childhood phase follows, which has a slowly decelerating velocity until puberty. The pubertal phase shows acceleration in GV and reaches a peak on average 22 months after initiation. GV then rapidly decreases and ceases.[79] This pubertal growth comprises 15-20% of final height (FH) and precedes fusion of the growth plates. Both the amplitude of the pubertal spurt and peak GV vary negatively with the age of onset of puberty.[79-81] Concordance is shown between the pubertal growth spurt and clinical pubertal development.[79,82,83] The tempo of pubertal growth shows sexual dimorphism. Growth acceleration is usually seen early with peak GV occurring at B2 in 40%, B3 in 30%, B4 in 20% and B1 in 10% of girls.[79] In contrast, there is an acceleration of growth usually during the second year of pubertal development with peak GV occurring at G3 in 60%, G4 in 28%, G2 in 8% and G5 in 4% in boys.[79] This dimorphic pattern may be related to the delay in boys reaching the level of oestrogen required (from aromatization of testosterone). Aromatization is mediated by aromatase (an enzyme of the cytochrome P450 group) whose function is to mediate the conversion of androgens to oestrogens.


The pubertal growth spurt is primarily due to increased secretion of the sex steroids, oestrogens and androgens. It has been widely accepted that oestrogen mediates pubertal bone growth in females; however, it has only recently been established that oestrogen, and not testosterone, mediates the same function for males. The growth patterns observed in certain rare syndromes suggest that, in humans, oestrogen is responsible for the initiation of the pubertal growth spurt and closure of the growth plate in both sexes. Inactivating mutations in either the ER-α gene or the aromatase gene in males have resulted in a lack of a pubertal growth spurt, absent epiphyseal closure with resultant tall stature (taller than predicted). The individual with a defective ER-α is unique.[84] He presented with tall stature, normal male sexual maturation, osteoporosis and open epiphyses. Treatment with oestrogen did not produce epiphyseal fusion nor improve his bone mineral density. A similar phenotype was described in a 24-year-old man with congenital aromatase deficiency who had tall stature, a bone age (BA) of 14 years and osteoporosis despite high testosterone levels.[85] Treatment with conjugated oestrogen for 6 months led to fusion of the growth plates and increased bone mineral density.[86] Aromatase deficiency has now been described in others and they all show persistent linear growth in adulthood with open epiphyseal growth plates.[87,88] Although data are limited, it has been reported that they seem to have an absent growth spurt and fusion of the growth plates occurs after treatment with exogenous oestrogen but not with testosterone.[87] 46,XY girls with complete androgen insensitivity syndrome (CAIS) do have a pubertal growth spurt, which tends to occur at a similar age and of similar amplitude to unaffected girls, thus, demonstrating that oestrogen is able to increase GV in the absence of androgens.[89]


Pubertal growth is influenced by the amount of body fat. In a longitudinal study of normal children, an additional body mass index (BMI) point (+1 kg) was reported to decrease the growth spurt by a mean of 0.5 cm and 0.9 cm, in girls and boys, respectively. However, FH was not affected due to the growth acceleration observed in childhood.[90]


It has been widely accepted that longitudinal growth ceases in late adolescence as a result of epiphyseal fusion, an abrupt event in which growth plate cartilage is replaced by bone tissue. However, careful observation suggests that growth ceases before fusion occurs[91,92] which suggests that fusion is the result of growth cessation.[92,93] The deceleration in longitudinal growth was previously attributed to a systemic mechanism. However, recent evidence indicates that it is caused by a local mechanism within the growth plate. In growth plate-transplantation studies, the growth rate of the transplanted growth plate depended on the age of the donor animal and not on that of the recipient.[94] This intrinsic mechanism has been referred to as "growth plate senescence".[95] The senescent decline in growth rate is mainly due to a decrease in the rate of chondrocyte proliferation in the growth plate.[96] Young rabbits treated with systemic dexamethasone for a 5-week period showed a reduction in longitudinal bone growth.[97] After recovery, their growth plates showed a delay in senescent decline in the growth rate, chondrocyte proliferation rate, growth plate height, PZ and hypertrophic zone (HZ) height.[97] This programmed senescence appears to be a function of proliferation.


Oestrogen is reported to accelerate the normal process of growth plate senescence, leading to earlier exhaustion of the growth plate and, as a consequence, earlier fusion.[92] However, this hypothesis was not supported by a recent study of castrated male rabbits[98] in which oestrogen was shown to decrease proliferation in the resting zone (RZ) chondrocytes. This latter study examined younger, male rabbits, which were treated for a shorter period of time (2 weeks compared to 8 weeks) and the plasma oestrogen levels achieved were much lower.


Disorders of Puberty that Lead to Growth Disturbance

Premature Sexual Maturation

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 and Thelarche Variant

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]


Isolated Premature Menarche

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]


Abnormalities of Adrenarche

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]


Central Precocious Puberty

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.


Gonadotrophin-independent Precocious Puberty

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 caf?-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]


Delayed Sexual Maturation

Primary Delay of Growth and Puberty

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.[120-123] 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]


Secondary Delay of Growth and Puberty

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.


Hypogonadal Endocrinopathy

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.


Hypogonadotrophic Hypogonadism

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]


Hypergonadotrophic Hypogonadism

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.


Hypogonadism with Other Endocrinopathy

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]


Disorders of Gonadal and Sexual Development

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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