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Early puberty in girls
Best Practice & Research Clinical Endocrinology and Metabolism Vol. 16, No. 1, pp. 153±163, 2002
doi:10.1053/beem.2002.0187, available online at http://www.idealibrary.com on
12 Early puberty in girls D. Mul*
MD, PhD
Paediatric Resident
W. Oostdijk{
MD, PhD
Paediatric Endocrinologist
S. L. S. Drop Professor of Paediatric Endocrinology Subdivision of Endocrinology, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands, {Ledien University Medical Centre, Department of Paediatrics, Leiden, 2300, RC. P.O. Box 9600, The Netherlands
Early puberty is not well de®ned in paediatric endocrinology. This chapter reviews the current insights on de®nitions, patient groups and treatment modalities in girls with early puberty. It is concluded that there is no clear evidence for a bene®cial eect of gonadotrophin releasing hormone agonist (GnRHa) treatment in auxological terms. A clinical approach is presented, including both auxological and psychological items. Further research is needed to answer the question of whether early puberty should be treated with GnRHa. Key words: early puberty; adopted children; precocious puberty; GnRHa treatment; short stature.
INTRODUCTION The paediatric endocrinologist is frequently asked whether pubertal development in a child is normal, early or too early (precocious). The recent public attention, mainly in the USA, on the subject of pubertal development and its earlier onset compared to some years ago, has also brought the clinician to re¯ect on the de®nitions of `normal', `early' and `precocious'.1±4 This review will deal with early puberty. Although in several studies children with `early puberty' have been included, so far no general de®nition of it has been accepted. A speci®c item concerns early puberty in adopted children. The above-mentioned changes in the normal age of onset of puberty do complicate the discussion as to whether early puberty is an existing entity or not. Another issue is the distinction between the non-progressive forms of central precocious puberty (CPP) and early puberty with respect to the auxological eects on growth and the need for gonadotrophin releasing hormone agonist (GnRHa) treatment. *All correspondence to D. Mul. E-mail: [email protected] 1521±690X/02/01015311 $35.00/00
c 2002 Elsevier Science Ltd. *
154 D. Mul et al
In this chapter we will review the literature on early puberty and provide guidelines to the clinical approach to children with early puberty. Since early puberty is most frequently seen in girls, most of the data presented concern girls.
DEFINITIONS Any de®nition of early or precocious puberty should be based on the normal age of onset of puberty in a population. In general the age limit for the de®nition of precocious puberty is 2 standard deviations (SDs) below the mean or median age of onset of puberty. For years, girls with an onset of puberty below 8 years of age were de®ned as having precocious puberty. Recently, in the USA the guidelines have been adapted so that children with an onset of puberty before 6 or 7 years of age (dependent on ethnicity) were advised to be evaluated for pathological aetiology.1 In Europe, no change in the current age limits have been proposed.2 Thus, the determination of what is normal or precocious, although based on statistical considerations, cannot escape from an element of arbitrariness.5 In fact, all girls starting puberty when aged 4 8 years can be regarded as having normal puberty, since their puberty starts within the statistical range of normality ( 2 to 2 SD). However, in clinical practice, children with an onset of puberty when just 4 8 years of age are frequently presented in the outpatient clinics. Several studies have included children with early puberty. No clear picture of how to de®ne early puberty can be derived from these studies. Some authors have used the age range 8± 10 years.6,7 Other authors have used ranges of between 7.5 and 8.5 years8, between 8 and 9 years9 or even 6±8 years.1 Even more confusing is the use of the words `early puberty' to include all types of puberty starting (too) early.10 Early puberty was described by Cassio et al8 as a `paraphysiological' condition, which refers to the trend towards earlier appearance of pubertal signs in several countries. In contrast, Lebrethon & Bourguignon9 argued that early puberty could be considered to be a diagnosis, being part of a spectrum of isosexual precocity in girls. Thus, there is a need for clear cut de®nitions. In this review, we de®ne early puberty in girls as the onset of puberty between 8 and 10 years of age. A recommendation for de®nitions is given in Table 1, (based on Lebrethon & Bourguignon9). It should be stressed that de®ning early puberty does not necessarily imply a need for any treatment in that age group nor should it be labelled as `pathology' per se. In the spectrum of early pubertal development a subgroup of patients has been described with precocious puberty (based on the age of onset of clinical signs of puberty) but with slow progression of further development.10,11 However, most of
Table 1. Recommended de®nitions. Age at onset of puberty in girls (years)
Precocious puberty (PP) slowly progressive PP Early puberty Normal puberty
Europe
USA
58 58 8±10 410
56 or 7 56 or 7 7±9 49
Early puberty in girls 155
these patients did not have luteinizing hormone (LH) peak values in the gonadotrophin releasing hormone (GnRH) stimulation test. Therefore, possibly these patients could be assigned to the early puberty group. A pubertal response in a GnRH stimulation test is an essential part of the de®nition of early puberty, especially when treatment with GnRHa is considered. We studied the gonadotrophin response after GnRH or GnRHa challenge in children with early puberty and found that more children demonstrated a pubertal pattern after GnRHa challenge compared to the response after native GnRH.12 Thus, any patient to whom GnRHa treatment is oered should, at least, have a pubertal response in any stimulation test (see Figure 1). As well as clinical development and gonadotrophin response, bone age (BA) could be used to de®ne early puberty, assuming that, comparable with precocious puberty, BA is advanced over chronological age. In the three studies mentioned below, BA advancement was approximately 1.6 years7, 1.2 years13 and 2 years.8
AUXOLOGICAL ASPECTS The deleterious eects of CPP on ®nal height are known from studies in children with CPP before the introduction of GnRHa.14,15 It seems that the normal compensatory mechanism (the younger the onset of puberty, the longer its duration16) cannot prevent height loss at ®nal height in these cases. In early puberty, there are few data only on the normal course of growth up to ®nal height. Cassio et al8 selected girls with an onset of puberty at 7.5±8.5 years of age. These girls were then randomized for either GnRHa treatment or no treatment.8 In the latter group, growth can be considered to be physiological, although a referral bias cannot be excluded. Their ®nal height was comparable with the target height. The untreated girls showed a fairly quick progression of pubertal signs and had menarche at a mean age of 10.8 yrs. In comparison, Ibanez et al13 studied 54 girls in Spain with an onset of puberty between 8 and 9 years of age (mean 8.6 years).13 In this group, FH ®nal height was in the target range. When the girls were divided into two groups according to birth weight, it appeared that, with a comparable target height, the girls with a birth weight of less than 1.5 standard deviation score (SDS) experienced menarche earlier and had a ®nal height of more than 5 cm (approx. 0.9 SDS) below the ®nal height in girls with birth weight of more than 1.5 SDS. The authors concluded that girls with reduced prenatal growth are not completely protected by the normal compensatory mechanism described above. They further suggested that children with early onset of puberty and low birth weight may be a subgroup of girls in which delay of pubertal development could be helpful. Bouvattier et al7 studied 30 girls with advanced puberty, of whom 10 were randomized for no GnRHa treatment. Here, advanced puberty was de®ned by the onset and rapid progression of pubertal signs between 8 and 10 years of age. In this group the clinical onset of puberty was observed at a mean age of 9.4 years. Menarche occurred at a mean age of 11.2 years. In the untreated group, ®nal height was 156.1 (SD 5.3) cm, which was not signi®cantly dierent from treated girls. The target height was 157.6 cm in this group.
156 D. Mul et al
Pubertal development girls: _ > B2 boys: testis volume _ > 4ml
Onset of puberty Girls < 8 yrs Boys < 9 yrs
Onset of puberty Girls 8–10 yrs Boys 9–11 yrs
Onset of puberty Girls > 10 yrs Boys > 11 yrs
No indication for GnRHa treatment unless GHD or mental retardation
ASSESS INDICATION FOR TREATMENT
Signs of sex steroid action · Clinical progression · HV increased · Pubertal pelvic ultrasound · BA > CA
Central activation Pubertal LH peak in GnRH (–a) stimulation test
3–6 months observation Rule out gonadotrophin independent PP No GnRHa treatment
Predicted adult height Age group:
DECISION
girls < 8 yrs boys < 9 yrs
Psychology
· Suffering · Teasing · Fear for menarche
girls 8–10 yrs boys 9–11 yrs
PAH compromised 1 Psychological reason GnRHa treatment 1
< -2SDs; , follow clinical course and PAH; , treatment in study, consider combination GnRHa and GH when PAH << - 2SDS, HV decreases or PAH deteriorates during GnRHa treatment.
Figure 1. Flow chart of the considerations involved with regard to the eventual initiation of treatment in children with early puberty. GnRHa, gonadotrophin releasing hormone agonist; GHD, growth hormone de®cient; HV, height velocity; BA, bone age; CA, chronological age; LH, luteinizing hormone; PP, precocious puberty; PAH, predicted adult height; SDS, standard deviation score. Reproduced with permission, from Mul12.
Early puberty in girls 157
PATIENT GROUPS Based on the normal distribution of the age of onset of puberty, a considerable number of children would ®t into the group of children with early puberty. However, in clinical practice there are three main groups that are brought to the attention of a paediatrician for evaluation and eventual treatment of early puberty: 1. Adopted children with early puberty, who are relatively short since they originate from countries with ®nal heights below the means in many Western countries. 2. Children with meningomyelocele or spina bi®da, entering puberty at an early age. 3. Other children with or without short stature, entering puberty at an early age. Adopted children It has been described in several European countries that adopted children from developing countries are over-represented among children suering from CPP or early puberty.17±23 Compared to an incidence of about 1/10 000 for idiopathic CPP, in Belgium 20±25% of children with CPP were adopted from developing countries.9,24 Together with other data from Belgium, the incidence of precocious puberty in adopted children was estimated to be 0.8±1.8%.25 However, the fact that adopted children may be under more cautious medical control may cause overestimation of these ®gures. In comparison to the normal age of menarche in the countries of origin, an early menarche is observed when the girls migrate to the Western world. In a sample of 107 girls from India, Proos et al17 showed that median menarcheal age was 11.6 years, whereas the normal median age of menarche in India varied from 12.8 years in privileged girls to 14.4 years in girls in rural areas. The same pattern of early menarche was observed by Oostdijk et al26 in the Netherlands. In 446 girls adopted from four dierent countries, mean age at menarche was 12.0 (SD 1.5) years, varying from 11.2 years in Indian girls to 12.4 years in girls from South Korea.26 The mean menarcheal age was signi®cantly lower than the mean for Dutch girls. In the studies of W. Oostdijk and L.A. Proos a positive correlation was found between menarcheal age and ®nal height. Although in bivariate correlation analysis later arrival in the Western world was associated with earlier menarche, in multiple regression analysis the menarcheal age was associated with height at arrival, but not with age at arrival.27,28 Height at arrival, the velocity of height catch-up growth and menarcheal age appeared to be signi®cantly correlated with ®nal height.28 In recent years, basic science has made progress in unravelling the mystery of the reawakening of the gonadotrophin releasing mechanisms in the brain at the onset of puberty. Terasawa & Fernandez29 extensively reviewed the neurobiological mechanisms of the onset of puberty. However, the cause of early onset of puberty in adopted children is still not known. One might speculate that early puberty in adopted children occurs as a result of changes in stimulatory and/or inhibitory neurotransmitter action, for example during transition from a situation with low socio-economic conditions to the highly auent Western world. In many adopted children this transition occurs in the neonatal period. This may be viewed as an important period since it is known that the GnRH neurosecretory system is already active in the neonatal period, whereafter inhibition will predominate.29 Possibly, environmental factors in the pre- or postnatal period have long term eects on the hypothalamo±pituitary action.30 Environmental in¯uences include the
158 D. Mul et al Table 2. Comparison between two prospective studies in adopted children combining GnRHa and GH treatment. Predicted Predicted BA height at start Duration of height at end Girls CA start start Prediction treatment treatment treatment (n) (years) (years) (method) (cm) (years) (cm) Mul et al40 GnRHa GnRHa GH
13 14
9.7 9.6
10.8 11.6
BP BP
149.3 146.8
3 3
155.6 157.0
Tuvemo et al41 GnRHa GnRHa GH
22 24
8.3 8.3
10.2 10.8
TW II TW II
163.6 163.1
2 2
162.6 164.9
CA, chronological age; BA, bone age; BP, Bailey & Pinneau; TW II, Tanner-Whitehouse II; GnRHa, gonadotrophin releasing hormone agonist; GH, growth hormone.
dietary change in adopted children from a low protein and low energy vegetarian diet to a balanced enriched diet after adoption.19 Furthermore, the presence of oestrogenlike substances in food (phyto-oestrogens)31 and other endocrine disrupters in their new environment and their in¯uence on the pubertal development of adopted children remains to be studied.32 Krstevska-Konstantinova et al25 have proposed organochlorine pesticide (e.g. DDT) involvement as an endocrine disrupter either by stimulation of oestrogen-sensitive tissues or by negative feedback inhibition of the gonadotrophins. The withdrawal of these substances following adoption would lead to the development of early or precocious puberty.25 In the last decade, the in¯uence of environmental factors on the timing of puberty in healthy Dutch children seems to be minimal, since no further decrease in the age of onset of puberty has been observed.33 Since it can be assumed that many adopted children are born to mothers from the lower social classes and are thus at risk for unfavourable circumstances in utero, the comparison of these adopted children with children born small for gestational age (SGA) is challenging. The long-term in¯uence of intra-uterine growth retardation on several endocrine axes has been described.34±39 With regard to the hypothalamicpituitary±gonadal axis, an earlier menopause and altered hypothalamic control of LH release were described to have an association with intra-uterine growth retardation.34,35 It can, therefore, be assumed that programming of the setting of the GnRH pulse generator is in¯uenced by prenatal factors. In The Netherlands and Sweden, prospective trials have studied the eect of treatment of early puberty in adopted children with either GnRHa alone or in combination with recombinant human growth hormone.40,41 A summary is provided in Table 2. The dierence in results between the two studies is dicult to explain. The method of bone age assessment and the prediction methods used may be part of the explanation for the dierence in initial height prediction. However, these methodological dierences between the studies probably do not account for the contrasting results after 2 or 3 years of study. From these preliminary data it can be concluded, at least for the Dutch study, that the addition of growth hormone to GnRHa treatment is eective for auxological reasons. However, ®nal height data are awaited for the ®nal conclusion on the eectiveness of this costly treatment. Furthermore, these studies lack a control group so that any conclusion has to be drawn with caution.
Early puberty in girls 159 Table 3. Results of treatment with GnRHa in short children. Bouvattier et al7 Cassio et al8 n Age at onset of puberty Age at start of Rx BA (years) PAH (cm) TH (cm) FH (cm) Duration of Rx (years) Method Eect
20 9.3 9.5 10.9 154.1 157.6 157.6 2 Prospective controlled FH TH
20 7.7 8.5 10.6 157.8 157.0 158.1 2 Prospective controlled FH 4 TH
Kauli et al47 Brauner et al48 7 8.6 9.4 12.4 147.1 150.3 2.1 Prospective uncontrolled FH 4 PAH
10 8.5 8.8 11.2 153.4 159.1 157.4 3.1 Prospective controlled PAH 5 FH 5 TH
Carel et al45 31 11.9 149.6 150.6* 2 Prospective uncontrolled
Source: Adapted, in part, from Bouvattier et al.7 Rx, treatment; BA, bone age; PAH, predicted adult height at start of treatment; TH, target height; FH, ®nal height; *FH prognosis.
Children with meningomyelocele or spina bi®da, entering puberty at an early age The cause of early puberty in children with meningomyelocele (MMCO) and/or spina bi®da is suggested to be due to local pressure or increased intracranial pressure stimulating the GnRH neurones, or that compression or stretch causes disruption of inhibitory ®bres.42 This group of patients is most frequently treated for psycho-social reasons, in order to prevent occurrence of menses. Growth data are in general dicult to obtain since height is not accurately measurable due to the paresis of the lower extremities in most children. Other children with or without short stature, entering puberty at an early age This group of children comprises children that are early maturers. In addition, they are sometimes already disadvantaged (in auxological terms) by short stature. Adopted children can also sometimes be classi®ed in this group. In general, there is no pathology present. Some argue that manipulation of the timing of puberty in this relatively normal age period for puberty is unlikely to aect ®nal height to any great extent.43 This is probably true when maturation occurs within a rather normal age range. Whether this holds for early maturers on the limits of the normal range is not known. Only a few studies have been reported on GnRHa treatment in children with early or normal puberty. A preliminary study by Municchi et al44 showed an improvement of 5.9 cm in height prediction after 4 years of treatment and of 6.4 cm compared to placebo treated patients. In contrast, Carel et al45 treated 31 girls for 2 years without a valuable improvement of near ®nal height. A remarkable ®nding in the latter study was the rapid progression of BA after discontinuation of treatment, causing a substantial decrease in height prediction. This phenomenon was also seen in children with precocious puberty after GnRHa treatment.46
160 D. Mul et al
Final height data can be derived from the studies of Cassio et al8 and Bouvattier et al and are, together with results from some other studies, summarized in Table 3. At this time, we do not know whether, in children with early puberty, the same pattern of growth after discontinuation of GnRHa treatment will be observed as was seen after GnRHa treatment for CPP. In precocious puberty, height gain can be estimated to be approximately 60±80% of the gain obtained at discontinuation of treatment.46,49±51 We conclude that in short children with early puberty, pubertal suppression does add a few centimetres at ®nal height compared to initial height prediction. No ®nal conclusion can be drawn as to whether GnRHa treatment is eective in children with short stature and early puberty. The amount of height gain raises questions on the balance between costs and burden for the child on the one hand and what is reached, in auxological terms, on the other hand. The results of large prospective studies in homogeneous groups of patients are needed before the indications for GnRHa treatment can be settled. 7
TREATMENT MODALITIES: INDICATIONS We have already described, above, the results of treatment with GnRHa in children with early puberty, with or without the addition of growth hormone. The results do not provide a clear picture on whether or not `success' is guaranteed from treatment. The reason is the heterogeneity of the patients who were included (age at onset of puberty, rate of progression of puberty etc), the variation in the duration of treatment and the relatively small numbers of patients in most studies. The main question, however, is what should be considered to be the `typical' patient with early puberty. However, some recommendations can be made for the general approach towards a child with early or precocious puberty. Figure 1 provides a ¯ow diagram. Important issues in this ¯ow chart include: . No GnRHa treatment in girls aged 410 years, unless there is a very speci®c reason (e.g. see Mul et al52). . Proof of activation of the GnRH pulse generator by the GnRH or GnRHa stimulation test should be present. . The decision to treat a child can be based on either psychological or auxological reasons. . Children with early puberty should be systematically folllowed up to answer the question of the eectiveness of treatment.
CONCLUSIONS Early puberty is described as the start of pubertal development between the ages of 8 and 10 years in girls. Activation of the hypothalamo±pituitary axis as well as bone age advancement should be present. In practice, adopted children are frequently aected by early puberty, compromising ®nal height. In other children with early puberty and relatively short stature the question of whether to treat them with GnRHa may also be raised. The results of GnRHa treatment in early puberty so far, cannot substantiate a `yes' or a `no' for this kind of treatment. The use of GnRHa treatment and also the addition of GH treatment in children with early puberty should be carefully monitored
Early puberty in girls 161
Practice points . in Europe, early puberty in girls is de®ned as the start of pubertal development between the ages of 8 and 10 years in girls. In the USA, other limits are used, with a lower limit of 6 or 7 years depending on ethnicity . adopted children frequently present with early puberty . not every child with early puberty needs GnRHa treatment . growth aspects and psychological issues can serve as an indication for treatment in children with early puberty . GnRHa treatment of early puberty is not yet established as an eective treatment
Research agenda . ®nal height data need to be obtained from ongoing studies and from children currently being treated with either GnRHa alone or with GnRHa and GH . research is needed to unravel the mechanism of early puberty in adopted children . genetic studies in children with dierent timing of pubertal development are required . the psychological aspects and quality of life in children with early puberty with or without GnRHa treatment need to be studied . the cost eectiveness of GnRHa treatment in short children needs to be evaluated . the use of aromatase inhibitors in early puberty should be investigated . the long term sequelae of GnRHa treatment need to be studied
and evaluated. Guidelines for the approach towards a child with early puberty are presented. Future research issues are provided in the research agenda. REFERENCES * 1. Kaplowitz PB & Ober®eld SE. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Reexamination of the age limit for de®ning when puberty is precocious in girls in the United States: implications for evaluation and treatment. Pediatrics 1999; 104: 936±941. * 2. Mul D, Fredriks AM, van Buuren S et al. Pubertal development in the Netherlands 1965±1997. Pediatric Research 2001; 50: 479±486. 3. Finlay F & Jones R. Precocious puberty. Pediatrics 2000; 106: 162±163. 4. Rosen®eld RL, Bachrach LK, Chernausek SD et al. Current age of onset of puberty. Pediatrics 2000; 106: 622±623. 5. Palmert MR & Boepple PA. Variation in the timing of puberty: clinical spectrum and genetic investigation. Journal of Clinical Endocrinology and Metabolism 2001; 86: 2364±2368. 6. Mul D, de Muinck Keizer-Schrama SM, Oostdijk W & Drop SL. Auxological and biochemical evaluation of pubertal suppression with the GnRH agonist leuprolide acetate in early and precocious puberty. Hormone Research 1999; 51: 270±276. * 7. Bouvattier C, Coste J, Rodrigue D et al. Lack of eect of GnRH agonists on ®nal height in girls with advanced puberty: a randomized long-term pilot study. Journal of Clinical Endocrinology and Metabolism 1999; 84: 3575±3578. * 8. Cassio A, Cacciari E, Balsamo A et al. Randomised trial of LHRH analogue treatment on ®nal height in girls with onset of puberty aged 7.5±8.5 years. Archives of Disease in Childhood 1999; 81: 329±332. 9. Lebrethon MC & Bourguignon JP. Management of central isosexual precocity: diagnosis, treatment, outcome. Current Opinion in Pediatrics 2000; 12: 394±399.
162 D. Mul et al 10. Palmert MR, Malin HV & Boepple PA. Unsustained or slowly progressive puberty in young girls: initial presentation and long-term follow-up of 20 untreated patients. Journal of Clinical Endocrinology and Metabolism 1999; 84: 415±423. 11. Fontoura M, Brauner R, Prevot C & Rappaport R. Precocious puberty in girls: early diagnosis of a slowly progressing variant. Archives of Disease in Childhood 1989; 64: 1170±1176. 12. Mul D. Treatment of early puberty in adopted and non-adopted children: when, why and how? PhD Thesis, Rotterdam: Erasmus University, 2000. 13. Ibanez L, Ferrer A, Marcos MV et al. Early puberty: rapid progression and reduced ®nal height in girls with low birth weight. Pediatrics 2000; 106: e72. 14. Sigurjonsdottir TJ & Hayles AB. Precocious puberty. A report of 96 cases. American Journal of Diseases of Children 1968; 115: 309±321. 15. Thamdrup E. Precocious Sexual Development. Copenhagen: Munksgaard, 1961. 16. Marti-Henneberg C & Vizmanos B. The duration of puberty in girls is related to the timing of its onset. Journal of Pediatrics 1997; 131: 618±621. 17. Proos LA, Hofvander Y & Tuvemo T. Menarcheal age and growth pattern of Indian girls adopted in Sweden. I Menarcheal age. Acta Paediatrica Scandinavica 1991; 80: 852±858. 18. Proos LA, Hofvander Y & Tuvemo T. Menarcheal age and growth pattern of Indian girls adopted in Sweden. II Catch-up growth and ®nal height. Indian Journal of Pediatrics 1991; 58: 105±114. 19. Virdis R, Street ME, Zampolli M et al. Precocious puberty in girls adopted from developing countries. Archives of Disease in Childhood 1998; 78: 15±154. 20. Marx M, Schoof E, Kapferer L & Dorr HG. Pubertas praecox vera bei einem indischen MaÈdchen nach Adoption durch deutsche Eltern. Monatsschrift Kinderheilkunde 1998; 146: 957±960. 21. Oostdijk W, Yap YN, Doude van Troostwijk ML et al. Final height and timing of puberty of adopted children in The Netherlands. Hormone Research 1991; 35: 24. 22. Oostdijk W, Yap YN, Rekers-Mombarg LTM et al. The impact of early puberty on ®nal height in foreign born, adopted children in The Netherlands. In Central Precocious Puberty and Gonadotropin Releasing Hormone Agonist Treatment, pp 135±150. Rotterdam: Erasmus University, 1996. Thesis. 23. Bureau JJ, Maurage C, Bremond M et al. Children of foreign origin adopted in France. Analysis of 68 cases during l2 years at the University Hospital Center of Tours. Archives de Pediatrie 1999; 6: 1053±1058 (In French). *24. Bourguignon JP, Gerard A, Alvarez Gonzales ML et al. Eects of changes in nutritional conditions on timing of puberty: clinical evidence from adopted children and experimental studies in the male rat. Hormone Research 1992; 38 (supplement 1): 97±105. 25. Krstevska-Konstantinova M, Charlier C, Craen M et al. Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Human Reproduction 2001; 16: 1020±1026. 26. Oostdijk W, Yap YN, Slijper FME et al. Puberteit en eindlengte bij uit het buitenland geadopteerde kinderen. Tijdschrift Kindergeneeskunde 1996; 64: 39±43. 27. Proos LA. Anthropometry in adolescence ± secular trends, adoption, ethnic and environmental dierences. Hormone Research 1993; 39 (supplement 3): 18±24. 28. Proos LA. Growth and Development of Indian Children Adopted in Sweden. PhD thesis, Uppsala, 1992. 29. Terasawa E & Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocrine Reviews 2001; 22: 111±151. 30. Cooper C, Kuh D, Egger P et al. Childhood growth and age at menarche. British Journal of Obstetrics and Gynaecology 1996; 103: 814±817. 31. Mazur W. Phytoestrogen content in foods. BaillieÁre's Clinical Endocrinology and Metabolism 1998; 12: 729±742. 32. Sharara FI, Seifer DB & Flaws JA. Environmental toxicants and female reproduction. Fertility and Sterility 1998; 70: 613±622. 33. Fredriks AM, van Buuren S, Burgmeijer RJ et al. Continuing positive secular growth change in The Netherlands 1955±1997. Pediatric Research 2000; 47: 316±323. 34. Cresswell JL, Barker DJ, Osmond C et al. Fetal growth, length of gestation, and polycystic ovaries in adult life. Lancet 1997; 350: 1131±1135. 35. Cresswell JL, Egger P, Fall CH et al. Is the age of menopause determined in-utero? Early Human Development 1997; 49: 143±148. 36. Clark PM, Hindmarsh PC, Shiell AW et al. Size at birth and adrenocortical function in childhood. Clinical Endocrinology (Oxford) 1996; 45: 721±726. 37. Fall CH, Pandit AN, Law CM et al. Size at birth and plasma insulin-like growth factor-1 concentrations. Archives of Disease in Childhood 1995; 73: 287±293. 38. Phillips DI, Barker DJ & Osmond C. Infant feeding, fetal growth and adult thyroid function. Acta Endocrinologica (Copenhagen) 1993; 129: 134±138.
Early puberty in girls 163 39. Law CM, Barker DJ, Osmond C et al. Early growth and abdominal fatness in adult life. Journal of Epidemiology and Community Health 1992; 46: 184±186. *40. Mul D, Oostdijk W, Waelkens JJJ & Drop SLS. Gonadotrophin releasing hormone agonist (GnRHa) treatment with or without recombinant human growth hormone (GH) in adopted children with early puberty. Clinical Endocrinology (Oxford) 2001; 55: 121±129. 41. Tuvemo T, Gustafsson J & Proos LA. Swedish Growth Hormone Advisory Group. Growth hormone treatment during suppression of early puberty in adopted girls. Acta Paediatrica 1999; 88: 928±932. 42. Abdolvahabi RM, Mitchell JA, Diaz FG & McAllister JP II. A brief review of the eects of chronic hydrocephalus on the gonadotropin releasing hormone system: implications for amenorrhea and precocious puberty. Neurological Research 2000; 22: 123±126. 43. Bourguignon JP and the Belgian Study Group for Paediatric Endocrinology. Variations in duration of pubertal growth: a mechanism compensating for dierences in timing of puberty and minimizing their eects on ®nal height. Acta Paediatrica Scandinavica 1988; 347: 16±24. 44. Municchi G, Rose SR, Pescovitz OH et al. Eects of Deslorelin-induced pubertal delay on the growth of adolescents with short stature and normally timed puberty: preliminary results. Journal of Clinical Endocrinology and Metabolism 1993; 77: 1334±1339. *45. Carel JC, Hay F, Coutant R et al. Gonadotropin-releasing hormone agonist treatment of girls with constitutional short stature and normal pubertal development. Journal of Clinical Endocrinology and Metabolism 1996; 81: 3318±3322. 46. Oostdijk W, Rikken B, Schreuder S et al. Final height in central precocious puberty after long-term treatment with a slow-release GnRH agonist. Archives of Disease in Childhood 1996; 75: 292±297. *47. Kauli R, Kornreich L & Laron Z. Pubertal development, growth and ®nal height in girls with sexual precocity after therapy with the GnRH analogue D-Trp-6-LHRH. Hormone Research 1990; 33: 11±17. *48. Brauner R, Malandry F, Zantleifer D & Adan L. Adult height in girls with idiopathic true precocious puberty. Journal of Clinical Endocrinology and Metabolism 1994; 79: 415±420. 49. Arrigo T, Cisternino M, Galluzzi F et al. Analysis of the factors aecting auxological response to GnRH agonist treatment and ®nal height outcome in girls with idiopathic central precocious puberty. European Journal of Endocrinology 1999; 141: 140±144. 50. Galluzzi F, Salti R, Pasquini E & La Cauza C. Adult height comparison between boys and girls with precocious puberty after long-term gonadotrophin-releasing hormone analogue therapy. Acta Paediatrica 1998; 87: 521±527. *51. Carel JC, Roger M, Ispas S et al. Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. Journal of Clinical Endocrinology and Metabolism 1999; 84: 1973±1978. 52. Mul D, Wit JM, Oostdijk W & Van den Broeck J. The eect of pubertal delay by GnRH agonist in growth hormone de®cient (GHD) children on ®nal height. Journal of Clinical Endocrinology and Metabolism 2001; 86: 4655±4656.
doi:10.1053/beem.2002.0187, available online at http://www.idealibrary.com on
12 Early puberty in girls D. Mul*
MD, PhD
Paediatric Resident
W. Oostdijk{
MD, PhD
Paediatric Endocrinologist
S. L. S. Drop Professor of Paediatric Endocrinology Subdivision of Endocrinology, Sophia Children's Hospital, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands, {Ledien University Medical Centre, Department of Paediatrics, Leiden, 2300, RC. P.O. Box 9600, The Netherlands
Early puberty is not well de®ned in paediatric endocrinology. This chapter reviews the current insights on de®nitions, patient groups and treatment modalities in girls with early puberty. It is concluded that there is no clear evidence for a bene®cial eect of gonadotrophin releasing hormone agonist (GnRHa) treatment in auxological terms. A clinical approach is presented, including both auxological and psychological items. Further research is needed to answer the question of whether early puberty should be treated with GnRHa. Key words: early puberty; adopted children; precocious puberty; GnRHa treatment; short stature.
INTRODUCTION The paediatric endocrinologist is frequently asked whether pubertal development in a child is normal, early or too early (precocious). The recent public attention, mainly in the USA, on the subject of pubertal development and its earlier onset compared to some years ago, has also brought the clinician to re¯ect on the de®nitions of `normal', `early' and `precocious'.1±4 This review will deal with early puberty. Although in several studies children with `early puberty' have been included, so far no general de®nition of it has been accepted. A speci®c item concerns early puberty in adopted children. The above-mentioned changes in the normal age of onset of puberty do complicate the discussion as to whether early puberty is an existing entity or not. Another issue is the distinction between the non-progressive forms of central precocious puberty (CPP) and early puberty with respect to the auxological eects on growth and the need for gonadotrophin releasing hormone agonist (GnRHa) treatment. *All correspondence to D. Mul. E-mail: [email protected] 1521±690X/02/01015311 $35.00/00
c 2002 Elsevier Science Ltd. *
154 D. Mul et al
In this chapter we will review the literature on early puberty and provide guidelines to the clinical approach to children with early puberty. Since early puberty is most frequently seen in girls, most of the data presented concern girls.
DEFINITIONS Any de®nition of early or precocious puberty should be based on the normal age of onset of puberty in a population. In general the age limit for the de®nition of precocious puberty is 2 standard deviations (SDs) below the mean or median age of onset of puberty. For years, girls with an onset of puberty below 8 years of age were de®ned as having precocious puberty. Recently, in the USA the guidelines have been adapted so that children with an onset of puberty before 6 or 7 years of age (dependent on ethnicity) were advised to be evaluated for pathological aetiology.1 In Europe, no change in the current age limits have been proposed.2 Thus, the determination of what is normal or precocious, although based on statistical considerations, cannot escape from an element of arbitrariness.5 In fact, all girls starting puberty when aged 4 8 years can be regarded as having normal puberty, since their puberty starts within the statistical range of normality ( 2 to 2 SD). However, in clinical practice, children with an onset of puberty when just 4 8 years of age are frequently presented in the outpatient clinics. Several studies have included children with early puberty. No clear picture of how to de®ne early puberty can be derived from these studies. Some authors have used the age range 8± 10 years.6,7 Other authors have used ranges of between 7.5 and 8.5 years8, between 8 and 9 years9 or even 6±8 years.1 Even more confusing is the use of the words `early puberty' to include all types of puberty starting (too) early.10 Early puberty was described by Cassio et al8 as a `paraphysiological' condition, which refers to the trend towards earlier appearance of pubertal signs in several countries. In contrast, Lebrethon & Bourguignon9 argued that early puberty could be considered to be a diagnosis, being part of a spectrum of isosexual precocity in girls. Thus, there is a need for clear cut de®nitions. In this review, we de®ne early puberty in girls as the onset of puberty between 8 and 10 years of age. A recommendation for de®nitions is given in Table 1, (based on Lebrethon & Bourguignon9). It should be stressed that de®ning early puberty does not necessarily imply a need for any treatment in that age group nor should it be labelled as `pathology' per se. In the spectrum of early pubertal development a subgroup of patients has been described with precocious puberty (based on the age of onset of clinical signs of puberty) but with slow progression of further development.10,11 However, most of
Table 1. Recommended de®nitions. Age at onset of puberty in girls (years)
Precocious puberty (PP) slowly progressive PP Early puberty Normal puberty
Europe
USA
58 58 8±10 410
56 or 7 56 or 7 7±9 49
Early puberty in girls 155
these patients did not have luteinizing hormone (LH) peak values in the gonadotrophin releasing hormone (GnRH) stimulation test. Therefore, possibly these patients could be assigned to the early puberty group. A pubertal response in a GnRH stimulation test is an essential part of the de®nition of early puberty, especially when treatment with GnRHa is considered. We studied the gonadotrophin response after GnRH or GnRHa challenge in children with early puberty and found that more children demonstrated a pubertal pattern after GnRHa challenge compared to the response after native GnRH.12 Thus, any patient to whom GnRHa treatment is oered should, at least, have a pubertal response in any stimulation test (see Figure 1). As well as clinical development and gonadotrophin response, bone age (BA) could be used to de®ne early puberty, assuming that, comparable with precocious puberty, BA is advanced over chronological age. In the three studies mentioned below, BA advancement was approximately 1.6 years7, 1.2 years13 and 2 years.8
AUXOLOGICAL ASPECTS The deleterious eects of CPP on ®nal height are known from studies in children with CPP before the introduction of GnRHa.14,15 It seems that the normal compensatory mechanism (the younger the onset of puberty, the longer its duration16) cannot prevent height loss at ®nal height in these cases. In early puberty, there are few data only on the normal course of growth up to ®nal height. Cassio et al8 selected girls with an onset of puberty at 7.5±8.5 years of age. These girls were then randomized for either GnRHa treatment or no treatment.8 In the latter group, growth can be considered to be physiological, although a referral bias cannot be excluded. Their ®nal height was comparable with the target height. The untreated girls showed a fairly quick progression of pubertal signs and had menarche at a mean age of 10.8 yrs. In comparison, Ibanez et al13 studied 54 girls in Spain with an onset of puberty between 8 and 9 years of age (mean 8.6 years).13 In this group, FH ®nal height was in the target range. When the girls were divided into two groups according to birth weight, it appeared that, with a comparable target height, the girls with a birth weight of less than 1.5 standard deviation score (SDS) experienced menarche earlier and had a ®nal height of more than 5 cm (approx. 0.9 SDS) below the ®nal height in girls with birth weight of more than 1.5 SDS. The authors concluded that girls with reduced prenatal growth are not completely protected by the normal compensatory mechanism described above. They further suggested that children with early onset of puberty and low birth weight may be a subgroup of girls in which delay of pubertal development could be helpful. Bouvattier et al7 studied 30 girls with advanced puberty, of whom 10 were randomized for no GnRHa treatment. Here, advanced puberty was de®ned by the onset and rapid progression of pubertal signs between 8 and 10 years of age. In this group the clinical onset of puberty was observed at a mean age of 9.4 years. Menarche occurred at a mean age of 11.2 years. In the untreated group, ®nal height was 156.1 (SD 5.3) cm, which was not signi®cantly dierent from treated girls. The target height was 157.6 cm in this group.
156 D. Mul et al
Pubertal development girls: _ > B2 boys: testis volume _ > 4ml
Onset of puberty Girls < 8 yrs Boys < 9 yrs
Onset of puberty Girls 8–10 yrs Boys 9–11 yrs
Onset of puberty Girls > 10 yrs Boys > 11 yrs
No indication for GnRHa treatment unless GHD or mental retardation
ASSESS INDICATION FOR TREATMENT
Signs of sex steroid action · Clinical progression · HV increased · Pubertal pelvic ultrasound · BA > CA
Central activation Pubertal LH peak in GnRH (–a) stimulation test
3–6 months observation Rule out gonadotrophin independent PP No GnRHa treatment
Predicted adult height Age group:
DECISION
girls < 8 yrs boys < 9 yrs
Psychology
· Suffering · Teasing · Fear for menarche
girls 8–10 yrs boys 9–11 yrs
PAH compromised 1 Psychological reason GnRHa treatment 1
< -2SDs; , follow clinical course and PAH; , treatment in study, consider combination GnRHa and GH when PAH << - 2SDS, HV decreases or PAH deteriorates during GnRHa treatment.
Figure 1. Flow chart of the considerations involved with regard to the eventual initiation of treatment in children with early puberty. GnRHa, gonadotrophin releasing hormone agonist; GHD, growth hormone de®cient; HV, height velocity; BA, bone age; CA, chronological age; LH, luteinizing hormone; PP, precocious puberty; PAH, predicted adult height; SDS, standard deviation score. Reproduced with permission, from Mul12.
Early puberty in girls 157
PATIENT GROUPS Based on the normal distribution of the age of onset of puberty, a considerable number of children would ®t into the group of children with early puberty. However, in clinical practice there are three main groups that are brought to the attention of a paediatrician for evaluation and eventual treatment of early puberty: 1. Adopted children with early puberty, who are relatively short since they originate from countries with ®nal heights below the means in many Western countries. 2. Children with meningomyelocele or spina bi®da, entering puberty at an early age. 3. Other children with or without short stature, entering puberty at an early age. Adopted children It has been described in several European countries that adopted children from developing countries are over-represented among children suering from CPP or early puberty.17±23 Compared to an incidence of about 1/10 000 for idiopathic CPP, in Belgium 20±25% of children with CPP were adopted from developing countries.9,24 Together with other data from Belgium, the incidence of precocious puberty in adopted children was estimated to be 0.8±1.8%.25 However, the fact that adopted children may be under more cautious medical control may cause overestimation of these ®gures. In comparison to the normal age of menarche in the countries of origin, an early menarche is observed when the girls migrate to the Western world. In a sample of 107 girls from India, Proos et al17 showed that median menarcheal age was 11.6 years, whereas the normal median age of menarche in India varied from 12.8 years in privileged girls to 14.4 years in girls in rural areas. The same pattern of early menarche was observed by Oostdijk et al26 in the Netherlands. In 446 girls adopted from four dierent countries, mean age at menarche was 12.0 (SD 1.5) years, varying from 11.2 years in Indian girls to 12.4 years in girls from South Korea.26 The mean menarcheal age was signi®cantly lower than the mean for Dutch girls. In the studies of W. Oostdijk and L.A. Proos a positive correlation was found between menarcheal age and ®nal height. Although in bivariate correlation analysis later arrival in the Western world was associated with earlier menarche, in multiple regression analysis the menarcheal age was associated with height at arrival, but not with age at arrival.27,28 Height at arrival, the velocity of height catch-up growth and menarcheal age appeared to be signi®cantly correlated with ®nal height.28 In recent years, basic science has made progress in unravelling the mystery of the reawakening of the gonadotrophin releasing mechanisms in the brain at the onset of puberty. Terasawa & Fernandez29 extensively reviewed the neurobiological mechanisms of the onset of puberty. However, the cause of early onset of puberty in adopted children is still not known. One might speculate that early puberty in adopted children occurs as a result of changes in stimulatory and/or inhibitory neurotransmitter action, for example during transition from a situation with low socio-economic conditions to the highly auent Western world. In many adopted children this transition occurs in the neonatal period. This may be viewed as an important period since it is known that the GnRH neurosecretory system is already active in the neonatal period, whereafter inhibition will predominate.29 Possibly, environmental factors in the pre- or postnatal period have long term eects on the hypothalamo±pituitary action.30 Environmental in¯uences include the
158 D. Mul et al Table 2. Comparison between two prospective studies in adopted children combining GnRHa and GH treatment. Predicted Predicted BA height at start Duration of height at end Girls CA start start Prediction treatment treatment treatment (n) (years) (years) (method) (cm) (years) (cm) Mul et al40 GnRHa GnRHa GH
13 14
9.7 9.6
10.8 11.6
BP BP
149.3 146.8
3 3
155.6 157.0
Tuvemo et al41 GnRHa GnRHa GH
22 24
8.3 8.3
10.2 10.8
TW II TW II
163.6 163.1
2 2
162.6 164.9
CA, chronological age; BA, bone age; BP, Bailey & Pinneau; TW II, Tanner-Whitehouse II; GnRHa, gonadotrophin releasing hormone agonist; GH, growth hormone.
dietary change in adopted children from a low protein and low energy vegetarian diet to a balanced enriched diet after adoption.19 Furthermore, the presence of oestrogenlike substances in food (phyto-oestrogens)31 and other endocrine disrupters in their new environment and their in¯uence on the pubertal development of adopted children remains to be studied.32 Krstevska-Konstantinova et al25 have proposed organochlorine pesticide (e.g. DDT) involvement as an endocrine disrupter either by stimulation of oestrogen-sensitive tissues or by negative feedback inhibition of the gonadotrophins. The withdrawal of these substances following adoption would lead to the development of early or precocious puberty.25 In the last decade, the in¯uence of environmental factors on the timing of puberty in healthy Dutch children seems to be minimal, since no further decrease in the age of onset of puberty has been observed.33 Since it can be assumed that many adopted children are born to mothers from the lower social classes and are thus at risk for unfavourable circumstances in utero, the comparison of these adopted children with children born small for gestational age (SGA) is challenging. The long-term in¯uence of intra-uterine growth retardation on several endocrine axes has been described.34±39 With regard to the hypothalamicpituitary±gonadal axis, an earlier menopause and altered hypothalamic control of LH release were described to have an association with intra-uterine growth retardation.34,35 It can, therefore, be assumed that programming of the setting of the GnRH pulse generator is in¯uenced by prenatal factors. In The Netherlands and Sweden, prospective trials have studied the eect of treatment of early puberty in adopted children with either GnRHa alone or in combination with recombinant human growth hormone.40,41 A summary is provided in Table 2. The dierence in results between the two studies is dicult to explain. The method of bone age assessment and the prediction methods used may be part of the explanation for the dierence in initial height prediction. However, these methodological dierences between the studies probably do not account for the contrasting results after 2 or 3 years of study. From these preliminary data it can be concluded, at least for the Dutch study, that the addition of growth hormone to GnRHa treatment is eective for auxological reasons. However, ®nal height data are awaited for the ®nal conclusion on the eectiveness of this costly treatment. Furthermore, these studies lack a control group so that any conclusion has to be drawn with caution.
Early puberty in girls 159 Table 3. Results of treatment with GnRHa in short children. Bouvattier et al7 Cassio et al8 n Age at onset of puberty Age at start of Rx BA (years) PAH (cm) TH (cm) FH (cm) Duration of Rx (years) Method Eect
20 9.3 9.5 10.9 154.1 157.6 157.6 2 Prospective controlled FH TH
20 7.7 8.5 10.6 157.8 157.0 158.1 2 Prospective controlled FH 4 TH
Kauli et al47 Brauner et al48 7 8.6 9.4 12.4 147.1 150.3 2.1 Prospective uncontrolled FH 4 PAH
10 8.5 8.8 11.2 153.4 159.1 157.4 3.1 Prospective controlled PAH 5 FH 5 TH
Carel et al45 31 11.9 149.6 150.6* 2 Prospective uncontrolled
Source: Adapted, in part, from Bouvattier et al.7 Rx, treatment; BA, bone age; PAH, predicted adult height at start of treatment; TH, target height; FH, ®nal height; *FH prognosis.
Children with meningomyelocele or spina bi®da, entering puberty at an early age The cause of early puberty in children with meningomyelocele (MMCO) and/or spina bi®da is suggested to be due to local pressure or increased intracranial pressure stimulating the GnRH neurones, or that compression or stretch causes disruption of inhibitory ®bres.42 This group of patients is most frequently treated for psycho-social reasons, in order to prevent occurrence of menses. Growth data are in general dicult to obtain since height is not accurately measurable due to the paresis of the lower extremities in most children. Other children with or without short stature, entering puberty at an early age This group of children comprises children that are early maturers. In addition, they are sometimes already disadvantaged (in auxological terms) by short stature. Adopted children can also sometimes be classi®ed in this group. In general, there is no pathology present. Some argue that manipulation of the timing of puberty in this relatively normal age period for puberty is unlikely to aect ®nal height to any great extent.43 This is probably true when maturation occurs within a rather normal age range. Whether this holds for early maturers on the limits of the normal range is not known. Only a few studies have been reported on GnRHa treatment in children with early or normal puberty. A preliminary study by Municchi et al44 showed an improvement of 5.9 cm in height prediction after 4 years of treatment and of 6.4 cm compared to placebo treated patients. In contrast, Carel et al45 treated 31 girls for 2 years without a valuable improvement of near ®nal height. A remarkable ®nding in the latter study was the rapid progression of BA after discontinuation of treatment, causing a substantial decrease in height prediction. This phenomenon was also seen in children with precocious puberty after GnRHa treatment.46
160 D. Mul et al
Final height data can be derived from the studies of Cassio et al8 and Bouvattier et al and are, together with results from some other studies, summarized in Table 3. At this time, we do not know whether, in children with early puberty, the same pattern of growth after discontinuation of GnRHa treatment will be observed as was seen after GnRHa treatment for CPP. In precocious puberty, height gain can be estimated to be approximately 60±80% of the gain obtained at discontinuation of treatment.46,49±51 We conclude that in short children with early puberty, pubertal suppression does add a few centimetres at ®nal height compared to initial height prediction. No ®nal conclusion can be drawn as to whether GnRHa treatment is eective in children with short stature and early puberty. The amount of height gain raises questions on the balance between costs and burden for the child on the one hand and what is reached, in auxological terms, on the other hand. The results of large prospective studies in homogeneous groups of patients are needed before the indications for GnRHa treatment can be settled. 7
TREATMENT MODALITIES: INDICATIONS We have already described, above, the results of treatment with GnRHa in children with early puberty, with or without the addition of growth hormone. The results do not provide a clear picture on whether or not `success' is guaranteed from treatment. The reason is the heterogeneity of the patients who were included (age at onset of puberty, rate of progression of puberty etc), the variation in the duration of treatment and the relatively small numbers of patients in most studies. The main question, however, is what should be considered to be the `typical' patient with early puberty. However, some recommendations can be made for the general approach towards a child with early or precocious puberty. Figure 1 provides a ¯ow diagram. Important issues in this ¯ow chart include: . No GnRHa treatment in girls aged 410 years, unless there is a very speci®c reason (e.g. see Mul et al52). . Proof of activation of the GnRH pulse generator by the GnRH or GnRHa stimulation test should be present. . The decision to treat a child can be based on either psychological or auxological reasons. . Children with early puberty should be systematically folllowed up to answer the question of the eectiveness of treatment.
CONCLUSIONS Early puberty is described as the start of pubertal development between the ages of 8 and 10 years in girls. Activation of the hypothalamo±pituitary axis as well as bone age advancement should be present. In practice, adopted children are frequently aected by early puberty, compromising ®nal height. In other children with early puberty and relatively short stature the question of whether to treat them with GnRHa may also be raised. The results of GnRHa treatment in early puberty so far, cannot substantiate a `yes' or a `no' for this kind of treatment. The use of GnRHa treatment and also the addition of GH treatment in children with early puberty should be carefully monitored
Early puberty in girls 161
Practice points . in Europe, early puberty in girls is de®ned as the start of pubertal development between the ages of 8 and 10 years in girls. In the USA, other limits are used, with a lower limit of 6 or 7 years depending on ethnicity . adopted children frequently present with early puberty . not every child with early puberty needs GnRHa treatment . growth aspects and psychological issues can serve as an indication for treatment in children with early puberty . GnRHa treatment of early puberty is not yet established as an eective treatment
Research agenda . ®nal height data need to be obtained from ongoing studies and from children currently being treated with either GnRHa alone or with GnRHa and GH . research is needed to unravel the mechanism of early puberty in adopted children . genetic studies in children with dierent timing of pubertal development are required . the psychological aspects and quality of life in children with early puberty with or without GnRHa treatment need to be studied . the cost eectiveness of GnRHa treatment in short children needs to be evaluated . the use of aromatase inhibitors in early puberty should be investigated . the long term sequelae of GnRHa treatment need to be studied
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