NEWS & VIEWS Treatment of girls with central precocious puberty Raja Brauner Refers to Silverman, L. A. et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: a final report of a phase 3 multicenter trial. J. Clin. Endocrinol. Metab. doi:10.1210/jc.2014-3031
Gonadotropin-releasing hormone analogues (GnRHa) can improve adult height prospects in children with central precocious puberty (CPP). A recent report demonstrates that 50 mg histrelin subcutaneous implants are safe and effective when used yearly. However, questions remain regarding the use of GnRHa in girls with idiopathic CPP, who experience a slow progressive form of puberty. Central precocious puberty (CPP) is defined as the development of sexual characteristics before the age of 8 years in girls and 9 years in boys due to premature activation of the hypothalamic–pituitary–gonadal axis. 1 In girls, CPP is idiopathic in 80% of cases, whereas CPP is due to a hypothalamic– pituitary insult in the majority of cases in boys.2 The premature secretion of estradiol in girls or testosterone in boys increases the growth rate and accelerates skeletal maturation, which can shorten the growing period and result in reduced adult height prospects. Treatment with gonadotropin-releasing hormone (GnRH) analogues (GnRHa) suppresses the hypothalamic–pituitary–gonadal axis and slows down puberty-induced skeletal maturation, thereby preserving the growth potential of affected individuals. Available GnRHa formulations vary by route of administration, dosage and duration of action, and are effective at achieving pubertal suppression and improving adult height projections in children with CPP.1,3 The 50 mg histrelin subcutaneous implant, used yearly in children with CPP, provides sustained suppression of puberty for 1 year.4 However, until the report by Silverman and colleagues,5 no detailed information on the safety and efficacy of histrelin subcutaneous implants beyond 2 years was available. The phase III open-label study by Silverman et al. included 36 children (33 girls and three boys) with CPP who had received up to 6 years of treatment and 1 year of follow-up after treatment.5 Hormonal suppression was achieved and maintained
‘‘
…the management of girls with idiopathic forms of CPP remains controversial…
’’
throughout the treatment period. Predicted adult height in girls increased from 151.9 cm to 166.5 cm over 5 years. Levels of gonado tropins increased to pubertal levels within 6 months of the removal of the last implant, thus signalling recovery of the hypothalamic– pituitary–gonadal axis. Implant site reactions were reported by 52.8% of patients over the 6 years of treatment. The authors concluded that long-term use of histrelin is safe and effectively improves the predicted adult height in children with CPP. However, the authors rightfully acknowledge several limitations in their study. Firstly, ethical considerations precluded the conduct of a placebo-controlled trial and forced the investigators to adopt an open-label study design. Secondly, half of the patients were pretreated with other forms of GnRHa before they were administered histrelin. Thirdly, use of predicted adult heights6 and not actual adult heights limited analysis of growth outcomes. Pubertal suppression using GnRHa has been known to improve the height out comes of children with CPP for several decades.3 However, the management of girls with idiopathic forms of CPP remains controversial, as a subset of these girls experience a slow progressive form of puberty in which the predicted adult height does not change within 2 years of the evolution of spontaneous puberty.7
NATURE REVIEWS | ENDOCRINOLOGY
Despite the breadth of reported data on adult height in girls with idiopathic CPP, major questions remain as to which indi viduals will benefit the most from several years of pubertal suppression. The reported height gain (defined as adult height minus predicted adult height at onset of treatment) after treatment with GnRHa in these patients has been shown to vary between 0.3 cm and 9.8 cm.3 The Consensus Conference Group on CPP recommends documentation of progressive pubertal development for 3–6 months before initiating treatment with GnRHa.1 To further guide the decision of whether to treat girls who have idio pathic CPP with GnRHa, my colleagues and I have proposed a mathematical model that estimates adult height using a formula that integrates the following parameters: height at baseline (± SD), target (mid-parental) height (± SD) and response to GnRH testing (peak level of luteinizing hormone [LH]:peak level of follicle-stimulating hormone [FSH] ratio).8 The time between onset of puberty and first menstruation after evolution of spontaneous puberty can also be estimated. This model was based on data from a cohort of 134 girls with idiopathic CPP, who underwent long-term follow-up.9 In our cohort, actual adult height was lower than calculated adult height by more than 1 SD (5.6 cm) in only 8% of girls studied.9 Both measurements were highly correlated (coefficient of correlation [r] 0.75), whereas predicted adult height obtained using the Bayley and Pinneau method6 was not as well correlated with actual adult height (r 0.55). This model has not yet been validated externally through testing in other cohorts. The yearly insertion of a histrelin implant might improve adherence to prescribed therapy and limit the medical burden on patients in comparison with monthly or
NPG
PAEDIATRIC ENDOCRINOLOGY
VOLUME 11 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS 3-monthly intramuscular GnRHa depot preparations. However, the commitment to yearly treatments can complicate the decision to discontinue therapy earlier than expected; for example, in patients who expe rience dramatically reduced growth rates during GnRHa treatment. Hence, histrelin implants might be particularly useful in very young children who are likely to need pubertal suppression for several years, such as patients with hypothalamic hamartoma.10
‘‘
Girls with idiopathic CPP … should be closely monitored until they reach a satisfactory height
’’
Precocious pubertal development poses several questions. Firstly, is the cause of precocious pubertal development central (hypothalamic–pituitary) or primary (gona dal)? Secondly, in central forms, is CPP organic (that is, related to a hypothalamic– pituitary insult such as tumour, radiation, hydrocephalus or malformations) or idio pathic? Thirdly, is treatment with GnRHa appropriate in girls with idiopathic CPP? In this group of patients, the decision to treat can be guided by patient characteristics (such as family history, target height, age,
JULY 2015 | VOLUME 11
psychosocial context, height at baseline and rate of pubertal development) and radiological and laboratory markers such as assessment of skeletal maturation (bone age) and the peak level of LH:peak level of FSH ratio after dynamic testing with GnRH.8 Although various forms of GnRHa treatments are available, the study by Silverman and colleagues confirms the safety and efficacy of the subcutaneous histrelin implant. Girls with idiopathic CPP, whether treated with GnRHa or not, should be closely monitored until they reach a satisfactory height. Université Paris Descartes and Fondation Ophtalmologique Adolphe de Rothschild, Unité d’Endocrinologie Pédiatrique, 25 Rue Manin, 75019 Paris, France. [email protected] doi:10.1038/nrendo.2015.65 Published online 28 April 2015 Competing interests The author declares no competing interests. 1.
2.
3.
Carel, J. C. et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 123, e752–e762 (2009). Chemaitilly, W. et al. Central precocious puberty: clinical and laboratory features. Clin. Endocrinol. (Oxf.) 54, 289–294 (2001). Willemsen, R. H., Elleri, D., Williams, R. M., Ong, K. K. & Dunger, D. B. Pros and cons of
GnRHa treatment for early puberty in girls. Nat. Rev. Endocrinol. 10, 352–363 (2014). 4. Eugster, E. A. et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J. Clin. Endocrinol. Metab. 92, 1697–1704 (2007). 5. Silverman, L. A. et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: a final report of a phase 3 multicenter trial. J. Clin. Endocrinol. Metab. http://dx.doi.org/10.1210/ jc.2014-3031. 6. Bayley, N. & Pinneau, S. R. Tables for predicting adult height from skeletal age: revised for use with the Greulich–Pyle hand standards. J. Pediatr. 40, 423–441 (1952). 7. Fontoura, M., Brauner, R., Prevot, C. & Rappaport, R. Precocious puberty in girls: early diagnosis of a slowly progressing variant. Arch. Dis. Child. 64, 1170–1176 (1989). 8. Oerter, K. E., Uriarte, M. M., Rose, S. R., Barnes, K. M. & Cutler, G. B. Jr. Gonadotropin secretory dynamics during puberty in normal girls and boys. J. Clin. Endocrinol. Metab. 71, 1251–1258 (1990). 9. Giabicani, E., Lemaire, P. & Brauner, R. Models for predicting the adult height and age at first menstruation of girls with idiopathic central precocious puberty. PLoS ONE 10, e0120588 (2015). 10. Bourayou, R., Giabicani, E., Pouillot, M., Brailly-Tabard, S. & Brauner, R. Premature pubarche before one year of age: distinguishing between mini-puberty variants and precocious puberty. Med. Sci. Monit. 21, 955–963 (2015).
www.nature.com/nrendo © 2015 Macmillan Publishers Limited. All rights reserved
Gonadotropin-releasing hormone analogues (GnRHa) can improve adult height prospects in children with central precocious puberty (CPP). A recent report demonstrates that 50 mg histrelin subcutaneous implants are safe and effective when used yearly. However, questions remain regarding the use of GnRHa in girls with idiopathic CPP, who experience a slow progressive form of puberty. Central precocious puberty (CPP) is defined as the development of sexual characteristics before the age of 8 years in girls and 9 years in boys due to premature activation of the hypothalamic–pituitary–gonadal axis. 1 In girls, CPP is idiopathic in 80% of cases, whereas CPP is due to a hypothalamic– pituitary insult in the majority of cases in boys.2 The premature secretion of estradiol in girls or testosterone in boys increases the growth rate and accelerates skeletal maturation, which can shorten the growing period and result in reduced adult height prospects. Treatment with gonadotropin-releasing hormone (GnRH) analogues (GnRHa) suppresses the hypothalamic–pituitary–gonadal axis and slows down puberty-induced skeletal maturation, thereby preserving the growth potential of affected individuals. Available GnRHa formulations vary by route of administration, dosage and duration of action, and are effective at achieving pubertal suppression and improving adult height projections in children with CPP.1,3 The 50 mg histrelin subcutaneous implant, used yearly in children with CPP, provides sustained suppression of puberty for 1 year.4 However, until the report by Silverman and colleagues,5 no detailed information on the safety and efficacy of histrelin subcutaneous implants beyond 2 years was available. The phase III open-label study by Silverman et al. included 36 children (33 girls and three boys) with CPP who had received up to 6 years of treatment and 1 year of follow-up after treatment.5 Hormonal suppression was achieved and maintained
‘‘
…the management of girls with idiopathic forms of CPP remains controversial…
’’
throughout the treatment period. Predicted adult height in girls increased from 151.9 cm to 166.5 cm over 5 years. Levels of gonado tropins increased to pubertal levels within 6 months of the removal of the last implant, thus signalling recovery of the hypothalamic– pituitary–gonadal axis. Implant site reactions were reported by 52.8% of patients over the 6 years of treatment. The authors concluded that long-term use of histrelin is safe and effectively improves the predicted adult height in children with CPP. However, the authors rightfully acknowledge several limitations in their study. Firstly, ethical considerations precluded the conduct of a placebo-controlled trial and forced the investigators to adopt an open-label study design. Secondly, half of the patients were pretreated with other forms of GnRHa before they were administered histrelin. Thirdly, use of predicted adult heights6 and not actual adult heights limited analysis of growth outcomes. Pubertal suppression using GnRHa has been known to improve the height out comes of children with CPP for several decades.3 However, the management of girls with idiopathic forms of CPP remains controversial, as a subset of these girls experience a slow progressive form of puberty in which the predicted adult height does not change within 2 years of the evolution of spontaneous puberty.7
NATURE REVIEWS | ENDOCRINOLOGY
Despite the breadth of reported data on adult height in girls with idiopathic CPP, major questions remain as to which indi viduals will benefit the most from several years of pubertal suppression. The reported height gain (defined as adult height minus predicted adult height at onset of treatment) after treatment with GnRHa in these patients has been shown to vary between 0.3 cm and 9.8 cm.3 The Consensus Conference Group on CPP recommends documentation of progressive pubertal development for 3–6 months before initiating treatment with GnRHa.1 To further guide the decision of whether to treat girls who have idio pathic CPP with GnRHa, my colleagues and I have proposed a mathematical model that estimates adult height using a formula that integrates the following parameters: height at baseline (± SD), target (mid-parental) height (± SD) and response to GnRH testing (peak level of luteinizing hormone [LH]:peak level of follicle-stimulating hormone [FSH] ratio).8 The time between onset of puberty and first menstruation after evolution of spontaneous puberty can also be estimated. This model was based on data from a cohort of 134 girls with idiopathic CPP, who underwent long-term follow-up.9 In our cohort, actual adult height was lower than calculated adult height by more than 1 SD (5.6 cm) in only 8% of girls studied.9 Both measurements were highly correlated (coefficient of correlation [r] 0.75), whereas predicted adult height obtained using the Bayley and Pinneau method6 was not as well correlated with actual adult height (r 0.55). This model has not yet been validated externally through testing in other cohorts. The yearly insertion of a histrelin implant might improve adherence to prescribed therapy and limit the medical burden on patients in comparison with monthly or
NPG
PAEDIATRIC ENDOCRINOLOGY
VOLUME 11 | JULY 2015 © 2015 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS 3-monthly intramuscular GnRHa depot preparations. However, the commitment to yearly treatments can complicate the decision to discontinue therapy earlier than expected; for example, in patients who expe rience dramatically reduced growth rates during GnRHa treatment. Hence, histrelin implants might be particularly useful in very young children who are likely to need pubertal suppression for several years, such as patients with hypothalamic hamartoma.10
‘‘
Girls with idiopathic CPP … should be closely monitored until they reach a satisfactory height
’’
Precocious pubertal development poses several questions. Firstly, is the cause of precocious pubertal development central (hypothalamic–pituitary) or primary (gona dal)? Secondly, in central forms, is CPP organic (that is, related to a hypothalamic– pituitary insult such as tumour, radiation, hydrocephalus or malformations) or idio pathic? Thirdly, is treatment with GnRHa appropriate in girls with idiopathic CPP? In this group of patients, the decision to treat can be guided by patient characteristics (such as family history, target height, age,
JULY 2015 | VOLUME 11
psychosocial context, height at baseline and rate of pubertal development) and radiological and laboratory markers such as assessment of skeletal maturation (bone age) and the peak level of LH:peak level of FSH ratio after dynamic testing with GnRH.8 Although various forms of GnRHa treatments are available, the study by Silverman and colleagues confirms the safety and efficacy of the subcutaneous histrelin implant. Girls with idiopathic CPP, whether treated with GnRHa or not, should be closely monitored until they reach a satisfactory height. Université Paris Descartes and Fondation Ophtalmologique Adolphe de Rothschild, Unité d’Endocrinologie Pédiatrique, 25 Rue Manin, 75019 Paris, France. [email protected] doi:10.1038/nrendo.2015.65 Published online 28 April 2015 Competing interests The author declares no competing interests. 1.
2.
3.
Carel, J. C. et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 123, e752–e762 (2009). Chemaitilly, W. et al. Central precocious puberty: clinical and laboratory features. Clin. Endocrinol. (Oxf.) 54, 289–294 (2001). Willemsen, R. H., Elleri, D., Williams, R. M., Ong, K. K. & Dunger, D. B. Pros and cons of
GnRHa treatment for early puberty in girls. Nat. Rev. Endocrinol. 10, 352–363 (2014). 4. Eugster, E. A. et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J. Clin. Endocrinol. Metab. 92, 1697–1704 (2007). 5. Silverman, L. A. et al. Long-term continuous suppression with once-yearly histrelin subcutaneous implants for the treatment of central precocious puberty: a final report of a phase 3 multicenter trial. J. Clin. Endocrinol. Metab. http://dx.doi.org/10.1210/ jc.2014-3031. 6. Bayley, N. & Pinneau, S. R. Tables for predicting adult height from skeletal age: revised for use with the Greulich–Pyle hand standards. J. Pediatr. 40, 423–441 (1952). 7. Fontoura, M., Brauner, R., Prevot, C. & Rappaport, R. Precocious puberty in girls: early diagnosis of a slowly progressing variant. Arch. Dis. Child. 64, 1170–1176 (1989). 8. Oerter, K. E., Uriarte, M. M., Rose, S. R., Barnes, K. M. & Cutler, G. B. Jr. Gonadotropin secretory dynamics during puberty in normal girls and boys. J. Clin. Endocrinol. Metab. 71, 1251–1258 (1990). 9. Giabicani, E., Lemaire, P. & Brauner, R. Models for predicting the adult height and age at first menstruation of girls with idiopathic central precocious puberty. PLoS ONE 10, e0120588 (2015). 10. Bourayou, R., Giabicani, E., Pouillot, M., Brailly-Tabard, S. & Brauner, R. Premature pubarche before one year of age: distinguishing between mini-puberty variants and precocious puberty. Med. Sci. Monit. 21, 955–963 (2015).
www.nature.com/nrendo © 2015 Macmillan Publishers Limited. All rights reserved
