Growth in precocious puberty
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《美国医学杂志》
1 Department of Endocrinology and Diabetes Royal Children's Hospital; Murdoch Children's Research Institute, Royal Children's Hospital, Australia
2 Department of Endocrinology and Diabetes Royal Children's Hospital; Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Abstract
Growth in precocious puberty is a subject of concern to families and clinicians alike. The definition of precocious puberty and the role of obesity in the age of onset have also been areas of debate since the Lawson Wilkins Society recommended a lowering of the age of onset of precocious puberty in US girls. An understanding of growth patterns in normal children with earlier or later onset of puberty and the variable rate of progression between individuals with central precocious puberty as well as the imprecision in available height prediction methods are important in assessing height outcomes in this condition. In the absence of randomised controlled trials in this area, only qualified conclusions about the effectiveness of interventions can be drawn. In general, it appears that height outcome is not compromised in untreated slowly progressive variants of central precocious puberty. In rapidly progressing central precocious puberty in girls, gonadotrophin releasing hormone agonists (GnRH agonists) appear to increase final height by about 5cm in girls treated before the age of eight, but there is no height benefit in those treated after eight years. Scanly data is available to assess treatment effects in boys. GnRH agonists appear to be relatively safe. The decision to treat central precocious puberty should take into account rate of progression of pubertal changes as well as biochemical markers and may need to address other factors (for example psychosocial and behavioural issues) as well as height outcome.
Keywords: Growth; Precocious puberty; Height; Gonadotrophin releasing hormone
Poor growth has been a longstanding concern in patients with precocious puberty. The definition of precocious puberty and role of obesity in the onset of puberty has recently come under review. Precocious puberty can occur in a number of different situations and these are highlighted. Establishing the type of precocious puberty and rate of progression are important in determining the need for treatment, if any. Here is reviewed the height outcome in central precocious puberty, untreated and treated, and the role of gonadotrophin releasing hormone agonists in management is discussed. Available data on treatment of secondary central precocious puberty in congenital adrenal hyperplasia is also discussed. A brief outline of the whole paper is given below, for better understanding.
Definition of Precocious Puberty
Role of obesity
Types of Precocious Puberty
Hypothyroidism
Precocious puberty associated with catch up growth
Precocious puberty in children migrating from developing countries
Variants of central precocious puberty
Treatment for precocious puberty
Indications for treatment in precocious puberty
Height outcome in untreated precocious puberty
Effect of treatment on final height
Growth hormone and GnRH agonist combined treatment
Treatment of central precocious puberty in Congenital Adrenal Hyperplasia
Adverse effects of GnRH treatment
Conclusions
Definition of Precocious Puberty
Until recently, it was widely accepted that puberty was precocious when secondary sexual characteristics developed before the age of 8 in girls and before the age of 9 in boys. It involves not only the physical changes of puberty, (delineated by the staging of Tanner 1962) but also linear growth acceleration and accelerated bone maturation. The basis for these recommendations is the data of Marshall and Tanner, based on longitudinal studies of white British boys and girls carried out in the 1960s.[1],[2]
The age definition of precocious puberty (PP) has recently been questioned. The US Pediatric Research in Office Settings (PROS) study[3] assessed a convenience sample of 17077 healthy girls aged 3 to 12 yr, seen in 65 predominantly suburban practices by clinicians participating in the PROS network. The study suggested that stage 2 of breast and pubic hair development occurred 1 year earlier in white girls and approximately 2 yr earlier in African American girls than what previous studies had shown. This study prompted the Lawson-Wilkins Pediatric Endocrine Society to issue new guidelines proposing that girls with either breast development or pubic hair development should be evaluated if this occurs before the age of 7 in white girls and before age 6 in African-American girls.[4] Nevertheless the PROS study and its conclusions remain controversial because of the unrepresentative nature of the sample, the lack of endocrine evaluation or follow up data to determine if any of the girls with earlier development had precocious puberty.[5],[6] In fact a recent report focusing on American girls aged 6 to 8 referred for evaluation of signs of puberty found that a significant proportion had true precocious puberty and specific associated diagnoses.[7]
A secular trend towards earlier onset of puberty has been noted in a number of countries, including Sweden,[8] Hong Kong[9] and the Netherlands,[6] although the trend appeared to be diminishing and stabilising in the latter 2 studies. Nevertheless, ethnically appropriate cut-offs for assessing sexual maturation (as recommended by the Lawson Wilkins society) may still be required since the third centile for breast stage 2 development in the Netherlands was 8.2 years, whereas in Hong Kong it was 7.10 years for Southern Chinese girls. Variations in the timing of puberty (onset/timing of menarche) are marked between well-off and underprivileged populations, with a marked delay in menarche reported in underprivileged girls.[10] These data highlight the role of socioeconomic and nutritional conditions in the timing of puberty. The variation in timing of puberty around the world has recently been reviewed.[11] A number of factors affecting this were explored, including the role of genetic factors, intrauterine conditions, nutrition and exposure to endocrine disrupting chemicals.
Role of obesity
An association between early sexual maturation and obesity is widely accepted, although the direction of causality has not been established.[12] The higher prevalence of obesity in the US has been cited as an explanation for the apparently earlier onset of sexual maturation in girls documented by Herman-Giddens et al . A reexamination of their data suggested that while obesity (as measured by BMI) was significantly associated with early puberty, the association was less strong in African-American girls than in white girls.[13] In their Dutch cohort Mul et al[6] found an association between increased weight (or BMI) and earlier age at menarche but no further reduction in age at menarche occurred beyond a weight or BMI of +1 SD. Interestingly Wang[12] found a negative association between obesity and sexual maturation in boys, namely thinner boys were maturing earlier.
Types of Precocious Puberty
Precocious puberty (PP) is classified as central, gonadotrophin dependent, when it results primarily from early hypothalamic-pituitary maturation. Central PP (CPP) represents 80% of cases of PP and occurs more commonly in girls, with a female to male ratio of at least 3:1.[14] Estimates of the frequency of CNS pathology causing central PP vary widely. In girls, estimates of idiopathic central PP range from 69-98%, compared to 0-60% in boys. [15],[16],[17],[18] These variations relate in part to improvements in neuroimaging but also to age at onset of PP. A recent study suggested that neuroimaging was overused and the majority of girls with CNS pathology had detectable neurological signs or symptoms.[19]
In peripheral, gonadotrophin-independent puberty, the primary event is increased secretion of adrenal or gonadal sex steroids or exposure to exogenous steroids. Some forms of peripheral PP occur in boys, such as chorionic gonadotrophin secreting tumors and familial gonadotrophin-independent peripheral PP resulting in constitutive activation of the LH receptor and hence testosterone production. Autonomous activation of the G protein stimulated cAMP formation and hence sex steroid production results in McCune Albright syndrome in girls.
Hypothyroidism
Hypothyroidism may also cause PP, although the mechanism for this is unclear. Interaction of TSH with the human FSH receptor is a possible pathophysiological mechanism for this syndrome, based on an in vitro FSH bioassay.[20] Hypothyroidism may also be associated with multicystic ovaries and PP, first documented by Van Wyk and Grumbach.[21] Treatment with thyroxine reverses both the PP and the ovarian cysts. Hypothyroidism should be excluded in girls with ovarian masses and PP to avoid unnecessary surgery.[22]
Precocious puberty associated with catch-up growth
Underfed children have delayed puberty. However, early sexual maturation has been observed in undernourished children who subsequently catch-up in height and weight.[11],[23] Hormonal events linked with catch-up growth may prime hypothalamic maturation and lead to puberty. The effect of early underfeeding and subsequent refeeding in a rat model of catch-up growth on hypothalamic glutamate neurotransmission was studied.[23] An acceleration of maturation of the glutamate receptor dependent GnRH secretion was observed after refeeding, suggesting an involvement of hypothalamic glutamate receptors in the pathophysiology of this form of sexual precocity.
Precocious puberty in children migrating from developing countries
First documented in Sweden[24] sexual precocity has been subsequently documented in children migrating to several European countries, mainly through international adoption (reviewed by Parent[11]), although the phenomenon has hardly been reported in the United States. Potential biases in reported studies include the use of early menarche to define sexual precocity and uncertain birth dates in some adopted children. In addition, parental concern regarding early sexual development of their adopted child may lead to over representation of early maturers among responders in questionnaire-based studies. Nevertheless, multiple reports from several countries suggest that early sexual maturation in this group is a robust finding. While sexual precocity in this group has been linked to undernutrition and catch-up growth (see above), the phenomenon has also been observed in adopted children who were not underweight, implicating factors other than nutrition with early sexual development.
Bajpai et al[25] reported the causes of PP seen in 140 patients referred to a tertiary centre in India. Female to male ratio was 4:1 and 95/140 had central PP. Defined causes of central PP, present in 55% of boys and 20% of girls, included neurotuberculosis, pituitary adenoma, hydrocephalus, post radiotherapy, CNS tumors and malformations.
Some forms of peripheral PP may evolve into central PP, including congenital adrenal hyperplasia (see below).
Variants of central precocious puberty
At least two variants of central precocious puberty can be recognised: true (rapidly progressive) PP and slowly progressive puberty. True PP is characterized by progression from one pubertal stage to the next in less than 6 months, accelerated growth velocity with a height prognosis below target height, or declining combined with evidence of activation of the hypothalamo-pituitary-gonadal (HPG) axis (LH predominant response to gonadotrophin releasing hormone (GnRH)). In contrast, slowly progressive PP shows stabilization or regression of pubertal signs, with a normal growth velocity for age without evidence of activation of the HPG axis.[26]
Pescovitz et al[27] have suggested a continuum of premature sexual development from isolated premature thelarche through to true PP which was divided into 6 groups based on clinical findings and gonadotrophin response to GnRH agonist table1. Importantly, this study reinforced the need for follow-up of individuals with findings of early sexual maturation. Girls with 'isolated' premature thelarche may develop central precocious puberty, and an FSH dominant response to GnRH does not exclude the presence of central PP. The activity of the HPG axis increases with the onset of puberty, with increased frequency and amplitude of spontaneous pulses of LH and FSH, plus increased peak levels in response to GnRH stimulation. Interpretation of pulsatile gonadotrophin activity is difficult because there is an overlap in spontaneous and stimulated levels of LH and FSH between prepubertal and pubertal children. In addition, levels of LH and FSH depend on the gonadotrophin assay used. The newer immunochemiluminometric assays (ICMA)[28] have much lower levels and a greater sensitivity than older radioimmunoassays. Caution should therefore be used in interpreting responses to GnRH stimulation in individuals being assessed for early sexual maturation.
Treatment for Precocious Puberty
Indications for treatment
There is no general consensus on the indications for treatment in PP. However, it is accepted that not all patients with CPP require treatment. The longterm a complication of true idiopathic PP commonly cited is a compromised adult height. Therefore, part of the decision of who to treat involves estimating final height. Some published data include hormonal/auxological criteria only.[29],[30] Other criteria include psychosocial or behavioral as possible reasons to treat.[5],[31] For example a 4 year old with periods may justify treatment even if her final height prediction is good. Similarly, a seven year old who is not mature enough to cope with emotional impact of puberty might be considered for treatment. A number of epidemiological studies have indicated that earlier menarche is associated with an increased risk of breast cancer.[32],[33] However, a recent Danish cohort study[34] has shown that (increased) growth during childhood and adolescence influences risk of breast cancer but that age at menarche is not an independent risk factor. The significance of an increased growth rate and age at menarche in precocious puberty in relation to breast cancer risk has not been evaluated.
Many children will require careful follow-up before a decision on the need for treatment can be made. The presence of clinical pubertal symptoms before the accepted age limits is not synonymous with PP but identifies patients who need further evaluation. GnRH agonist treatment is not indicated on auxological grounds in patients with no evidence of pubertal gonadotrophin secretion and with slowly progressing PP. In the case of uncompromised height, potential additional indications need to be present to justify treatment.
Height prediction in PP
Height prediction in PP is difficult and relies on height prediction algorithms, the most widely used being the Bayley-Pinneau method.[35] This estimates adult height based on current height, chronological age and bone age. In PP, the precision is unsatisfactory; there is a systematic error with an overestimation of adult height in girls of between 3.7[36] to 5.9 cm.[37] In addition, the standard deviation of the difference between observed and predicted height is 4.5 cm, with differences ranging from -4 to +13 cm.[38] In boys, scanty data is available but imprecision of height estimation using the Bayley-Pinneau method is even greater.[39] Kelnar and Stanhope[40] also agree that bone age predictions are inaccurate, but argue that nonlinearity in bone age advance in puberty results in a misleadingly low predicted adult height, thus leading to an overestimate of any treatment effect on final height.
PP and height outcome (untreated)
Assessing the outcome of precocious puberty is contingent on an understanding of growth in normal puberty and the variants of precocious puberty. Before puberty, growth velocity declines progressively with age. After the prepubertal decline, growth velocity increases, reaching a peak on an average 22 months later.[41] The total pubertal growth spurt is not a fixed value but varies inversely with age at onset of puberty.[41] Similarly, peak growth velocity decreases with age at onset of puberty.[42] Thus there is usually a compensatory mechanism whereby those who enter puberty earlier start puberty shorter but grow more during puberty, whereas those who enter puberty later are taller before puberty and grow less during puberty. The completeness of this compensation is debated. A study in Spanish boys entering puberty at 11, 13 and 15 demonstrated equivalent final height[43], whereas an American study in girls with earlier vs later menarche demonstrated an increased final height in girls (2.6cm) with later menarche.[44] These compensatory mechanisms appear to be extended to slowly progressive variants of PP, since untreated individuals with slowly progressive PP have a good spontaneous height prognosis.[30],[45],[46] A number of historical series demonstrate the effect of untreated true PP, indicating a poor height outcome, with mean heights of 152 cm in girls and 156 cm in males. However, this data should be treated with caution this is they are derived from a small number of patients whose disease severity may be worse than many patients seen today, and the data do not account for the secular increase in height. Published data for height outcome in untreated boys and girls is shown in table2.
Effect of treatment on final height
The choice of treatment for PP depends on its underlying cause. For those with idiopathic true PP and those with CPP secondary to chronic stimulation of the HPG axis treatment is given to suppress gonadotrophin secretion. GnRH agonists, preferably given in depot form, have become the treatment of choice due to effective suppression of pituitary gonadotrophin secretion and thus gonadal sex steroid secretion. A number of studies have now reported final height in treated patients table3table4. Evaluating the effect of GnRH agonists on final height is difficult. Ideally, a randomized controlled trial comparing height outcome in treated and untreated patients is required, but no such study exists. First, patients treated for PP are a heterogeneous group, with varying age of onset, progression of pubertal development and other factors influencing growth. Second, indirect methods are used to evaluate height benefit, comparing height outcome with the Bayley-Pinneau method and with historical controls, both of which have their limitations. Overall, the results of studies suggest a positive effect on GnRH agonist treatment in individuals with true central PP, with evidence of activation of the HPG axis. The exact benefit is difficult to assess, for the reasons given above, but the mean increase in adult height in girls is at least 5 cm, and probably more, given that prediction methods tend to overestimate the untreated height prognosis.
Effect of age at start of GnRH treatment.
It might be expected that earlier onset of treatment would increase final height. When treatment is started after the age of 8 yr, there is no beneficial effect on final height.[47] Of interest is the effect of treatment in the age range 6-8 yr, close the age limit recently discussed for the definition of PP. In fact, in most studies, the mean age at initiation of treatment is between 6 and 8 yr. In a subgroup analysis, Carel et al [26] found no difference in mean height gain in those in whom treatment was started between 6 and 8 and those treated before the age of 6. They found no statistical association between age at onset of puberty or at initiation of treatment and adult height gain or final height.
Growth hormone and GnRH agonist combined treatment
GnRH agonist treatment slows bone age progression as well as growth velocity. Addition of growth hormone, in non-growth hormone deficient patients was postulated to increase growth velocity and thus enhance final height. In a non-randomized study, Pucarelli[48] compared 17 patients with CPP treated with growth hormone and a GnRH analogue with 18 patients with CPP who refused GH treatment. The combination of Growth Hormone and GnRH agonist appeared to increase final height by a mean of 6 cm compared to GnRH treatment alone, with marked variability in height gain. The authors comment that use of the GH/GnRH combination is invasive and expensive and appears safe but should only be used at present in a research setting.
Progestational agents
The use of progestational agents such as cyproterone acetate or medroxyprogesterone acetate for treatment of PP has become less common, because these drugs are relatively ineffective with regard to hormonal suppression and height outcome.[49] Nevertheless, in situations where the primary aim is to suppress menstruation and not to improve final height, progestagens may be a more cost effective alternative.
Treatment of Central Precocious Puberty in Congenital Adrenal Hyperplasia
Secondary CPP in CAH has long been recognized and is mainly seen in late diagnosed individuals or inadequately treated patients continuously exposed to high levels of adrenal androgens. Early reports describe the use of cyproterone acetate,[50] and subsequently the use of GnRH agonists.[17], [51] Dacou-Voutetakis[52] reported height outcome in 4 late diagnosed patients with CAH treated with GnRH agonists compared to 4 late diagnosed patients with CAH who were not treated with a GnRH agonist. In this non-randomised study, final height in the GnRH agonist treated group was not different from target height, whereas in the control group, final height was significantly less than target height (p <0.05). Soliman[53] reported reduction in growth velocity and increases in predicted adult height in 6 CAH patients with CPP treated with GnRH agonists. Analysis of auxological data during the first 2 years of life showed that linear growth was significantly accelerated and bone age was advanced in patients who developed CPP compared with 11 age-matched patients. More recently, the combination of growth hormone and GnRH agonist treatment of patients with CAH and early puberty has been described.[54] In this uncontrolled study involving 8 patients, improvements in predicted adult height were described, but final height data was not available. In view of small numbers reported and the uncontrolled nature of interventions, benefits of GnRH agonists with or without concomitant growth hormone therapy in CAH remain uncertain.
Adverse effects of GnRH treatment
Side effects reported with GnRH agonist treatment include minor menopausal symptoms in girls (headache, nausea, hot flushes) in 2-5% of patients, local allergic reactions in upto 10% of patients and formation of sterile abscesses at the injection site. Weight gain during treatment has been a concern. Although obesity is common at the onset of PP (see above) it does not appear to be worsened by GnRH agonist treatment.[55] Another potential concern is effect of GnRH treatment on bone mineral density by reducing sex steroid levels, leading to a situation of hypoestrogenism that may have a detrimental effect on bone mass during pubertal development. With advanced bone age at diagnosis of PP, bone mineral density may be increased. However, bone mineral density at the end, at final height is within the normal range.[56],[57],[58] Nevertheless, calcium supplementation leads to a significant increase in bone mineral density and may improve peak bone mass.[58]
Conclusion
Many studies have been performed which indicate that treatment with GnRH agonist improves final height in rapidly progressive central precocious puberty in girls. Unfortunately, in the absence of placebo-controlled randomized trials, the magnitude of the treatment effect is unclear, thus estimates have been derived by comparison with historical controls and imprecise height prediction methods. There appears to be no benefit in treating girls above 8 yr of age, the traditional cut off age for the definition of PP. However there are height benefits of treatment in the age range 6 to 8 years where there is biochemical evidence of HPG axis activation, an age range which overlaps with the recently revised age definition for PP proposed by Kaplowitz and Oberfield.[6] In contrast, there is no benefit in treating girls with slowly progressive precocious puberty. In view of smaller numbers of treated boys with PP, the treatment benefits are less clear, but compared to historical controls, final height appears to be improved. Overall the side effects of treatment with GnRH agonists appear to be minor, and concerns about effects on obesity and bone mineral density have not been sustained[74].
Abbrevations
PP = precocious puberty
CPP = central precocious puberty
HPG = hypothalamo-pituitary-gonadal axis
BMI = Body mass index
GnRH = gonadotrophin releasing hormone
CAH = congenital adrenal hyperplasia
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49. Sorgo W, Kiraly E, Homoki J, Heinze E, Teller WM, Bierich JR, Moeller H, Ranke MB, Butenandt O, Knorr D. The effects of cyproterone acetate on statural growth in children with precocious puberty. Acta Endocrinol (Copenh) 1987; 115(1) : 44-56.
50. Beyer J, Demisch K, Wiegelmann W, Happ J, Kollmann F, Schoffling K. Cyproterone acetate in the treatment of infantile adrenogenital syndrome with precocious puberty. Acta Endocrinol Suppl (Copenh) 1973; 173 : 169.
51. Pescovitz OH, Comite F, Cassorla F, Dwyer AJ, Poth MA, Sperling MA, Hench K, McNemar A, Skerda M, Loriaux DL et al. True precocious puberty complicating congenital adrenal hyperplasia: treatment with a luteinizing hormone-releasing hormone analog. J Clin Endocrinol Metab 1984; 58(5) : 857-861.
52. Dacou-Voutetakis C, Karidis N. Congenital adrenal hyperplasia complicated by central precocious puberty: treatment with LHRH-agonist analogue. Ann N Y Acad Sci 1993; 687:250-254.
53. Soliman AT, AlLamki M, AlSalmi I, Asfour M. Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog. Metabolism 1997; 46(5) : 513-517.
54. Quintos JB, Vogiatzi MG, Harbison MD, New MI. Growth hormone therapy alone or in combination with gonadotropin-releasing hormone analog therapy to improve the height deficit in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86(4) : 1511-1517.
55. Palmert MR, Mansfield MJ, Crowley WF Jr, Crigler JF Jr, Crawford JD, Boepple PA. Is obesity an outcome of gonadotropin-releasing hormone agonist administration Analysis of growth and body composition in 110 patients with central precocious puberty. J Clin Endocrinol Metab 1999; 84(12) : 4480-4488.
56. Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab 1999; 84(12) : 4583-4590. [Erratum in: J Clin Endocrinol Metab 2000; 85(2) : 657.]
57. Bertelloni S, Baroncelli GI, Sorrentino MC, Perri G, Saggese G. Effect of central precocious puberty and gonadotropin-releasing hormone analogue treatment on peak bone mass and final height in females. Eur J Pediatr 1998; 157(5) : 363-367.
58. Antoniazzi F, Zamboni G, Bertoldo F, Lauriola S, Mengarda F, Pietrobelli A, Tato L. Bone mass at final height in precocious puberty after gonadotropin-releasing hormone agonist with and without calcium supplementation. J Clin Endocrinol Metab 2003; 88(3) : 1096-1101.
59. Sigurjonsdottir TJ, Hayles AB. Precocious puberty. A report of 96 cases. Am J Dis Child 1968; 115(3) : 309-321.
60. Bovier-Lapierre M, Sempe M, David M. [Etiological, clinical and biological aspects of precocious puberty of central origin] Pediatrie 1972; 27(6) : 587-609. [Article in French]
61. Werder EA, Murset G, Zachmann M, Brook CG, Prader A. Treatment of precocious puberty with cyproterone acetate. Pediatr Res 1974; 8(4) : 248-256.
62. Lee PA. Medroxyprogesterone therapy for sexual precocity in girls. Am J Dis Child 1981; 135(5) : 443-445.
63. Schoevaart CE, Drop SL, Otten BJ, Slijper FM, Degenhart HJ. Growth analysis up to final height and psychosocial adjustment of treated and untreated patients with precocious puberty. Horm Res 1990; 34(5-6) : 197-203.
64. Paul D, Conte FA, Grumbach MM, Kaplan SL. Long-term effect of gonadotropin-releasing hormone agonist therapy on final and near-final height in 26 children with true precocious puberty treated at a median age of less than 5 years. J Clin Endocrinol Metab 1995; 80(2) : 546-551.
65. Kauli R, Kornreich L, Laron Z. Pubertal development, growth and final height in girls with sexual precocity after therapy with the GnRH analogue D-TRP-6-LHRH. A report on 15 girls, followed after cessation of gonadotrophin suppressive therapy. Horm Res 1990; 33(1) : 11-17.
66. Brauner R, Adan L, Malandry F, Zantleifer D. Adult height in girls with idiopathic true precocious puberty. J Clin Endocrinol Metab 1994; 79(2) : 415-420.
67. Oostdijk W, Rikken B, Schreuder S, Otten B, Odink R, Rouwe C, Jansen M, Gerver WJ, Waelkens J, Drop S. Final height in central precocious puberty after long term treatment with a slow release GnRH agonist. Arch Dis Child 1996; 75(4) : 292-297.
68. Galluzzi F, Salti R, Bindi G, Pasquini E, La Cauza C. Adult height comparison between boys and girls with precocious puberty after long-term gonadotrophin-releasing hormone analogue therapy. Acta Paediatr 1998; 87(5) : 521-527.
69. Arrigo T, Cisternino M, Galluzzi F, Bertelloni S, Pasquino AM, Antoniazzi F, Borrelli P, Crisafulli G, Wasniewska M, De Luca F. Analysis of the factors affecting auxological response to GnRH agonist treatment and final height outcome in girls with idiopathic central precocious puberty. Eur J Endocrinol 1999; 141(2) : 140-144.
70. Cassio A, Cacciari E, Balsamo A, Bal M, Tassinari D. Randomised trial of LHRH analogue treatment on final height in girls with onset of puberty aged 7.5-8.5 years. Arch Dis Child 1999; 81(4) : 329-332.
71. Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler GB Jr. Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience. J Clin Endocrinol Metab 2001; 86(10) : 4711-4716.
72. Adan L, Chemaitilly W, Trivin C, Brauner R. Factors predicting adult height in girls with idiopathic central precocious puberty: implications for treatment. Clin Endocrinol (Oxf) 2002; 56(3) : 297-302.
73. Mul D, Bertelloni S, Carel JC, Saggese G, Chaussain JL, Oostdijk W. Effect of gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty: final height results. Horm Res 2002; 58(1) : 1-7.
74. Rizzo V, De Sanctis V, Corrias A, Fortini M, Galluzzi F, Bertelloni S, Guarneri MP, Pozzan G, Cisternino M, Pasquino AM. Factors influencing final/near-final height in 12 boys with central precocious puberty treated with gonadotrophin-releasing hormone agonists. Italian Study Group of Physiopathology of Puberty. J Pediatr Endocrinol Metab 2000;13 Suppl 1 : 781-786.(Brown Justin J, Warne Gar)
2 Department of Endocrinology and Diabetes Royal Children's Hospital; Murdoch Children's Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
Abstract
Growth in precocious puberty is a subject of concern to families and clinicians alike. The definition of precocious puberty and the role of obesity in the age of onset have also been areas of debate since the Lawson Wilkins Society recommended a lowering of the age of onset of precocious puberty in US girls. An understanding of growth patterns in normal children with earlier or later onset of puberty and the variable rate of progression between individuals with central precocious puberty as well as the imprecision in available height prediction methods are important in assessing height outcomes in this condition. In the absence of randomised controlled trials in this area, only qualified conclusions about the effectiveness of interventions can be drawn. In general, it appears that height outcome is not compromised in untreated slowly progressive variants of central precocious puberty. In rapidly progressing central precocious puberty in girls, gonadotrophin releasing hormone agonists (GnRH agonists) appear to increase final height by about 5cm in girls treated before the age of eight, but there is no height benefit in those treated after eight years. Scanly data is available to assess treatment effects in boys. GnRH agonists appear to be relatively safe. The decision to treat central precocious puberty should take into account rate of progression of pubertal changes as well as biochemical markers and may need to address other factors (for example psychosocial and behavioural issues) as well as height outcome.
Keywords: Growth; Precocious puberty; Height; Gonadotrophin releasing hormone
Poor growth has been a longstanding concern in patients with precocious puberty. The definition of precocious puberty and role of obesity in the onset of puberty has recently come under review. Precocious puberty can occur in a number of different situations and these are highlighted. Establishing the type of precocious puberty and rate of progression are important in determining the need for treatment, if any. Here is reviewed the height outcome in central precocious puberty, untreated and treated, and the role of gonadotrophin releasing hormone agonists in management is discussed. Available data on treatment of secondary central precocious puberty in congenital adrenal hyperplasia is also discussed. A brief outline of the whole paper is given below, for better understanding.
Definition of Precocious Puberty
Role of obesity
Types of Precocious Puberty
Hypothyroidism
Precocious puberty associated with catch up growth
Precocious puberty in children migrating from developing countries
Variants of central precocious puberty
Treatment for precocious puberty
Indications for treatment in precocious puberty
Height outcome in untreated precocious puberty
Effect of treatment on final height
Growth hormone and GnRH agonist combined treatment
Treatment of central precocious puberty in Congenital Adrenal Hyperplasia
Adverse effects of GnRH treatment
Conclusions
Definition of Precocious Puberty
Until recently, it was widely accepted that puberty was precocious when secondary sexual characteristics developed before the age of 8 in girls and before the age of 9 in boys. It involves not only the physical changes of puberty, (delineated by the staging of Tanner 1962) but also linear growth acceleration and accelerated bone maturation. The basis for these recommendations is the data of Marshall and Tanner, based on longitudinal studies of white British boys and girls carried out in the 1960s.[1],[2]
The age definition of precocious puberty (PP) has recently been questioned. The US Pediatric Research in Office Settings (PROS) study[3] assessed a convenience sample of 17077 healthy girls aged 3 to 12 yr, seen in 65 predominantly suburban practices by clinicians participating in the PROS network. The study suggested that stage 2 of breast and pubic hair development occurred 1 year earlier in white girls and approximately 2 yr earlier in African American girls than what previous studies had shown. This study prompted the Lawson-Wilkins Pediatric Endocrine Society to issue new guidelines proposing that girls with either breast development or pubic hair development should be evaluated if this occurs before the age of 7 in white girls and before age 6 in African-American girls.[4] Nevertheless the PROS study and its conclusions remain controversial because of the unrepresentative nature of the sample, the lack of endocrine evaluation or follow up data to determine if any of the girls with earlier development had precocious puberty.[5],[6] In fact a recent report focusing on American girls aged 6 to 8 referred for evaluation of signs of puberty found that a significant proportion had true precocious puberty and specific associated diagnoses.[7]
A secular trend towards earlier onset of puberty has been noted in a number of countries, including Sweden,[8] Hong Kong[9] and the Netherlands,[6] although the trend appeared to be diminishing and stabilising in the latter 2 studies. Nevertheless, ethnically appropriate cut-offs for assessing sexual maturation (as recommended by the Lawson Wilkins society) may still be required since the third centile for breast stage 2 development in the Netherlands was 8.2 years, whereas in Hong Kong it was 7.10 years for Southern Chinese girls. Variations in the timing of puberty (onset/timing of menarche) are marked between well-off and underprivileged populations, with a marked delay in menarche reported in underprivileged girls.[10] These data highlight the role of socioeconomic and nutritional conditions in the timing of puberty. The variation in timing of puberty around the world has recently been reviewed.[11] A number of factors affecting this were explored, including the role of genetic factors, intrauterine conditions, nutrition and exposure to endocrine disrupting chemicals.
Role of obesity
An association between early sexual maturation and obesity is widely accepted, although the direction of causality has not been established.[12] The higher prevalence of obesity in the US has been cited as an explanation for the apparently earlier onset of sexual maturation in girls documented by Herman-Giddens et al . A reexamination of their data suggested that while obesity (as measured by BMI) was significantly associated with early puberty, the association was less strong in African-American girls than in white girls.[13] In their Dutch cohort Mul et al[6] found an association between increased weight (or BMI) and earlier age at menarche but no further reduction in age at menarche occurred beyond a weight or BMI of +1 SD. Interestingly Wang[12] found a negative association between obesity and sexual maturation in boys, namely thinner boys were maturing earlier.
Types of Precocious Puberty
Precocious puberty (PP) is classified as central, gonadotrophin dependent, when it results primarily from early hypothalamic-pituitary maturation. Central PP (CPP) represents 80% of cases of PP and occurs more commonly in girls, with a female to male ratio of at least 3:1.[14] Estimates of the frequency of CNS pathology causing central PP vary widely. In girls, estimates of idiopathic central PP range from 69-98%, compared to 0-60% in boys. [15],[16],[17],[18] These variations relate in part to improvements in neuroimaging but also to age at onset of PP. A recent study suggested that neuroimaging was overused and the majority of girls with CNS pathology had detectable neurological signs or symptoms.[19]
In peripheral, gonadotrophin-independent puberty, the primary event is increased secretion of adrenal or gonadal sex steroids or exposure to exogenous steroids. Some forms of peripheral PP occur in boys, such as chorionic gonadotrophin secreting tumors and familial gonadotrophin-independent peripheral PP resulting in constitutive activation of the LH receptor and hence testosterone production. Autonomous activation of the G protein stimulated cAMP formation and hence sex steroid production results in McCune Albright syndrome in girls.
Hypothyroidism
Hypothyroidism may also cause PP, although the mechanism for this is unclear. Interaction of TSH with the human FSH receptor is a possible pathophysiological mechanism for this syndrome, based on an in vitro FSH bioassay.[20] Hypothyroidism may also be associated with multicystic ovaries and PP, first documented by Van Wyk and Grumbach.[21] Treatment with thyroxine reverses both the PP and the ovarian cysts. Hypothyroidism should be excluded in girls with ovarian masses and PP to avoid unnecessary surgery.[22]
Precocious puberty associated with catch-up growth
Underfed children have delayed puberty. However, early sexual maturation has been observed in undernourished children who subsequently catch-up in height and weight.[11],[23] Hormonal events linked with catch-up growth may prime hypothalamic maturation and lead to puberty. The effect of early underfeeding and subsequent refeeding in a rat model of catch-up growth on hypothalamic glutamate neurotransmission was studied.[23] An acceleration of maturation of the glutamate receptor dependent GnRH secretion was observed after refeeding, suggesting an involvement of hypothalamic glutamate receptors in the pathophysiology of this form of sexual precocity.
Precocious puberty in children migrating from developing countries
First documented in Sweden[24] sexual precocity has been subsequently documented in children migrating to several European countries, mainly through international adoption (reviewed by Parent[11]), although the phenomenon has hardly been reported in the United States. Potential biases in reported studies include the use of early menarche to define sexual precocity and uncertain birth dates in some adopted children. In addition, parental concern regarding early sexual development of their adopted child may lead to over representation of early maturers among responders in questionnaire-based studies. Nevertheless, multiple reports from several countries suggest that early sexual maturation in this group is a robust finding. While sexual precocity in this group has been linked to undernutrition and catch-up growth (see above), the phenomenon has also been observed in adopted children who were not underweight, implicating factors other than nutrition with early sexual development.
Bajpai et al[25] reported the causes of PP seen in 140 patients referred to a tertiary centre in India. Female to male ratio was 4:1 and 95/140 had central PP. Defined causes of central PP, present in 55% of boys and 20% of girls, included neurotuberculosis, pituitary adenoma, hydrocephalus, post radiotherapy, CNS tumors and malformations.
Some forms of peripheral PP may evolve into central PP, including congenital adrenal hyperplasia (see below).
Variants of central precocious puberty
At least two variants of central precocious puberty can be recognised: true (rapidly progressive) PP and slowly progressive puberty. True PP is characterized by progression from one pubertal stage to the next in less than 6 months, accelerated growth velocity with a height prognosis below target height, or declining combined with evidence of activation of the hypothalamo-pituitary-gonadal (HPG) axis (LH predominant response to gonadotrophin releasing hormone (GnRH)). In contrast, slowly progressive PP shows stabilization or regression of pubertal signs, with a normal growth velocity for age without evidence of activation of the HPG axis.[26]
Pescovitz et al[27] have suggested a continuum of premature sexual development from isolated premature thelarche through to true PP which was divided into 6 groups based on clinical findings and gonadotrophin response to GnRH agonist table1. Importantly, this study reinforced the need for follow-up of individuals with findings of early sexual maturation. Girls with 'isolated' premature thelarche may develop central precocious puberty, and an FSH dominant response to GnRH does not exclude the presence of central PP. The activity of the HPG axis increases with the onset of puberty, with increased frequency and amplitude of spontaneous pulses of LH and FSH, plus increased peak levels in response to GnRH stimulation. Interpretation of pulsatile gonadotrophin activity is difficult because there is an overlap in spontaneous and stimulated levels of LH and FSH between prepubertal and pubertal children. In addition, levels of LH and FSH depend on the gonadotrophin assay used. The newer immunochemiluminometric assays (ICMA)[28] have much lower levels and a greater sensitivity than older radioimmunoassays. Caution should therefore be used in interpreting responses to GnRH stimulation in individuals being assessed for early sexual maturation.
Treatment for Precocious Puberty
Indications for treatment
There is no general consensus on the indications for treatment in PP. However, it is accepted that not all patients with CPP require treatment. The longterm a complication of true idiopathic PP commonly cited is a compromised adult height. Therefore, part of the decision of who to treat involves estimating final height. Some published data include hormonal/auxological criteria only.[29],[30] Other criteria include psychosocial or behavioral as possible reasons to treat.[5],[31] For example a 4 year old with periods may justify treatment even if her final height prediction is good. Similarly, a seven year old who is not mature enough to cope with emotional impact of puberty might be considered for treatment. A number of epidemiological studies have indicated that earlier menarche is associated with an increased risk of breast cancer.[32],[33] However, a recent Danish cohort study[34] has shown that (increased) growth during childhood and adolescence influences risk of breast cancer but that age at menarche is not an independent risk factor. The significance of an increased growth rate and age at menarche in precocious puberty in relation to breast cancer risk has not been evaluated.
Many children will require careful follow-up before a decision on the need for treatment can be made. The presence of clinical pubertal symptoms before the accepted age limits is not synonymous with PP but identifies patients who need further evaluation. GnRH agonist treatment is not indicated on auxological grounds in patients with no evidence of pubertal gonadotrophin secretion and with slowly progressing PP. In the case of uncompromised height, potential additional indications need to be present to justify treatment.
Height prediction in PP
Height prediction in PP is difficult and relies on height prediction algorithms, the most widely used being the Bayley-Pinneau method.[35] This estimates adult height based on current height, chronological age and bone age. In PP, the precision is unsatisfactory; there is a systematic error with an overestimation of adult height in girls of between 3.7[36] to 5.9 cm.[37] In addition, the standard deviation of the difference between observed and predicted height is 4.5 cm, with differences ranging from -4 to +13 cm.[38] In boys, scanty data is available but imprecision of height estimation using the Bayley-Pinneau method is even greater.[39] Kelnar and Stanhope[40] also agree that bone age predictions are inaccurate, but argue that nonlinearity in bone age advance in puberty results in a misleadingly low predicted adult height, thus leading to an overestimate of any treatment effect on final height.
PP and height outcome (untreated)
Assessing the outcome of precocious puberty is contingent on an understanding of growth in normal puberty and the variants of precocious puberty. Before puberty, growth velocity declines progressively with age. After the prepubertal decline, growth velocity increases, reaching a peak on an average 22 months later.[41] The total pubertal growth spurt is not a fixed value but varies inversely with age at onset of puberty.[41] Similarly, peak growth velocity decreases with age at onset of puberty.[42] Thus there is usually a compensatory mechanism whereby those who enter puberty earlier start puberty shorter but grow more during puberty, whereas those who enter puberty later are taller before puberty and grow less during puberty. The completeness of this compensation is debated. A study in Spanish boys entering puberty at 11, 13 and 15 demonstrated equivalent final height[43], whereas an American study in girls with earlier vs later menarche demonstrated an increased final height in girls (2.6cm) with later menarche.[44] These compensatory mechanisms appear to be extended to slowly progressive variants of PP, since untreated individuals with slowly progressive PP have a good spontaneous height prognosis.[30],[45],[46] A number of historical series demonstrate the effect of untreated true PP, indicating a poor height outcome, with mean heights of 152 cm in girls and 156 cm in males. However, this data should be treated with caution this is they are derived from a small number of patients whose disease severity may be worse than many patients seen today, and the data do not account for the secular increase in height. Published data for height outcome in untreated boys and girls is shown in table2.
Effect of treatment on final height
The choice of treatment for PP depends on its underlying cause. For those with idiopathic true PP and those with CPP secondary to chronic stimulation of the HPG axis treatment is given to suppress gonadotrophin secretion. GnRH agonists, preferably given in depot form, have become the treatment of choice due to effective suppression of pituitary gonadotrophin secretion and thus gonadal sex steroid secretion. A number of studies have now reported final height in treated patients table3table4. Evaluating the effect of GnRH agonists on final height is difficult. Ideally, a randomized controlled trial comparing height outcome in treated and untreated patients is required, but no such study exists. First, patients treated for PP are a heterogeneous group, with varying age of onset, progression of pubertal development and other factors influencing growth. Second, indirect methods are used to evaluate height benefit, comparing height outcome with the Bayley-Pinneau method and with historical controls, both of which have their limitations. Overall, the results of studies suggest a positive effect on GnRH agonist treatment in individuals with true central PP, with evidence of activation of the HPG axis. The exact benefit is difficult to assess, for the reasons given above, but the mean increase in adult height in girls is at least 5 cm, and probably more, given that prediction methods tend to overestimate the untreated height prognosis.
Effect of age at start of GnRH treatment.
It might be expected that earlier onset of treatment would increase final height. When treatment is started after the age of 8 yr, there is no beneficial effect on final height.[47] Of interest is the effect of treatment in the age range 6-8 yr, close the age limit recently discussed for the definition of PP. In fact, in most studies, the mean age at initiation of treatment is between 6 and 8 yr. In a subgroup analysis, Carel et al [26] found no difference in mean height gain in those in whom treatment was started between 6 and 8 and those treated before the age of 6. They found no statistical association between age at onset of puberty or at initiation of treatment and adult height gain or final height.
Growth hormone and GnRH agonist combined treatment
GnRH agonist treatment slows bone age progression as well as growth velocity. Addition of growth hormone, in non-growth hormone deficient patients was postulated to increase growth velocity and thus enhance final height. In a non-randomized study, Pucarelli[48] compared 17 patients with CPP treated with growth hormone and a GnRH analogue with 18 patients with CPP who refused GH treatment. The combination of Growth Hormone and GnRH agonist appeared to increase final height by a mean of 6 cm compared to GnRH treatment alone, with marked variability in height gain. The authors comment that use of the GH/GnRH combination is invasive and expensive and appears safe but should only be used at present in a research setting.
Progestational agents
The use of progestational agents such as cyproterone acetate or medroxyprogesterone acetate for treatment of PP has become less common, because these drugs are relatively ineffective with regard to hormonal suppression and height outcome.[49] Nevertheless, in situations where the primary aim is to suppress menstruation and not to improve final height, progestagens may be a more cost effective alternative.
Treatment of Central Precocious Puberty in Congenital Adrenal Hyperplasia
Secondary CPP in CAH has long been recognized and is mainly seen in late diagnosed individuals or inadequately treated patients continuously exposed to high levels of adrenal androgens. Early reports describe the use of cyproterone acetate,[50] and subsequently the use of GnRH agonists.[17], [51] Dacou-Voutetakis[52] reported height outcome in 4 late diagnosed patients with CAH treated with GnRH agonists compared to 4 late diagnosed patients with CAH who were not treated with a GnRH agonist. In this non-randomised study, final height in the GnRH agonist treated group was not different from target height, whereas in the control group, final height was significantly less than target height (p <0.05). Soliman[53] reported reduction in growth velocity and increases in predicted adult height in 6 CAH patients with CPP treated with GnRH agonists. Analysis of auxological data during the first 2 years of life showed that linear growth was significantly accelerated and bone age was advanced in patients who developed CPP compared with 11 age-matched patients. More recently, the combination of growth hormone and GnRH agonist treatment of patients with CAH and early puberty has been described.[54] In this uncontrolled study involving 8 patients, improvements in predicted adult height were described, but final height data was not available. In view of small numbers reported and the uncontrolled nature of interventions, benefits of GnRH agonists with or without concomitant growth hormone therapy in CAH remain uncertain.
Adverse effects of GnRH treatment
Side effects reported with GnRH agonist treatment include minor menopausal symptoms in girls (headache, nausea, hot flushes) in 2-5% of patients, local allergic reactions in upto 10% of patients and formation of sterile abscesses at the injection site. Weight gain during treatment has been a concern. Although obesity is common at the onset of PP (see above) it does not appear to be worsened by GnRH agonist treatment.[55] Another potential concern is effect of GnRH treatment on bone mineral density by reducing sex steroid levels, leading to a situation of hypoestrogenism that may have a detrimental effect on bone mass during pubertal development. With advanced bone age at diagnosis of PP, bone mineral density may be increased. However, bone mineral density at the end, at final height is within the normal range.[56],[57],[58] Nevertheless, calcium supplementation leads to a significant increase in bone mineral density and may improve peak bone mass.[58]
Conclusion
Many studies have been performed which indicate that treatment with GnRH agonist improves final height in rapidly progressive central precocious puberty in girls. Unfortunately, in the absence of placebo-controlled randomized trials, the magnitude of the treatment effect is unclear, thus estimates have been derived by comparison with historical controls and imprecise height prediction methods. There appears to be no benefit in treating girls above 8 yr of age, the traditional cut off age for the definition of PP. However there are height benefits of treatment in the age range 6 to 8 years where there is biochemical evidence of HPG axis activation, an age range which overlaps with the recently revised age definition for PP proposed by Kaplowitz and Oberfield.[6] In contrast, there is no benefit in treating girls with slowly progressive precocious puberty. In view of smaller numbers of treated boys with PP, the treatment benefits are less clear, but compared to historical controls, final height appears to be improved. Overall the side effects of treatment with GnRH agonists appear to be minor, and concerns about effects on obesity and bone mineral density have not been sustained[74].
Abbrevations
PP = precocious puberty
CPP = central precocious puberty
HPG = hypothalamo-pituitary-gonadal axis
BMI = Body mass index
GnRH = gonadotrophin releasing hormone
CAH = congenital adrenal hyperplasia
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