Treatment of precocious puberty
- Jennifer Harrington, MBBS, PhD
Jennifer Harrington, MBBS, PhD
- Department of Pediatrics, University of Toronto
- Division of Endocrinology, Hospital for Sick Children
- Mark R Palmert, MD, PhD
Mark R Palmert, MD, PhD
- Department of Pediatrics, University of Toronto
- Division of Endocrinology, Hospital for Sick Children
- Section Editors
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
- Mitchell E Geffner, MD
Mitchell E Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
- Deputy Editors
- Alison G Hoppin, MD
Alison G Hoppin, MD
- Deputy Editor — Pediatrics
- Assistant Professor of Pediatrics, part time
- Harvard Medical School
- Kathryn A Martin, MD
Kathryn A Martin, MD
- Senior Deputy Editor — UpToDate
- Deputy Editor — Endocrinology and Patient Education
- Assistant Professor of Medicine
- Harvard Medical School
Precocious puberty is traditionally defined as the onset of secondary sexual development before the age of eight years in girls and nine years in boys. Because of trends towards earlier pubertal development, some healthy girls will have breast or pubic hair development before this age, and extensive evaluation and treatment may not be required. If the evaluation leads to a diagnosis of progressive precocious puberty, treatment may be considered.
The treatment of precocious puberty, which depends upon the underlying cause, will be discussed in this topic. The definition, etiology, and evaluation of precocious puberty are reviewed separately. (See "Definition, etiology, and evaluation of precocious puberty".)
Precocious puberty can be classified based upon the underlying pathologic process.
●Central precocious puberty — Central precocious puberty (CPP, also known as gonadotropin-dependent precocious puberty or true precocious puberty) is caused by early maturation of the hypothalamic-pituitary-gonadal (HPG) axis. It is characterized by sequential maturation of breasts and pubic hair in girls, and of maturation of the testes, penis, and pubic hair in boys. The sexual characteristics are appropriate for the child's gender (isosexual). CPP is idiopathic in 80 to 90 percent of cases in girls, whereas intracranial lesions are detected in 40 to 75 percent of boys with CPP (table 1A). (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of central precocious puberty (CPP)'.)
●Peripheral precocity — Peripheral precocity (also known as gonadotropin-independent precocious puberty or peripheral precocious puberty) is caused by excess secretion of sex hormones (estrogens or androgens) derived either from the gonads or adrenal glands, exogenous sources of sex steroids, or ectopic production of gonadotropins from a germ cell tumor (eg, human chorionic gonadotropin, hCG) (table 1B). We use the term precocity instead of puberty because puberty implies activation of the HPG axis, as occurs in CPP, whereas precocity refers only to the secondary sexual characteristics. Peripheral precocity is most commonly either isosexual (concordant with the child's gender), or contrasexual (with virilization of girls and feminization of boys), but can also present with both virilizing and feminizing features in rare cases. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)
- Lahlou N, Carel JC, Chaussain JL, Roger M. Pharmacokinetics and pharmacodynamics of GnRH agonists: clinical implications in pediatrics. J Pediatr Endocrinol Metab 2000; 13 Suppl 1:723.
- Boepple PA, Mansfield MJ, Wierman ME, et al. Use of a potent, long acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty. Endocr Rev 1986; 7:24.
- Crowley WF Jr, Comite F, Vale W, et al. Therapeutic use of pituitary desensitization with a long-acting lhrh agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab 1981; 52:370.
- Mahachoklertwattana P, Kaplan SL, Grumbach MM. The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history. J Clin Endocrinol Metab 1993; 77:118.
- Striano S, Santulli L, Ianniciello M, et al. The gelastic seizures-hypothalamic hamartoma syndrome: facts, hypotheses, and perspectives. Epilepsy Behav 2012; 24:7.
- Carel JC, Léger J. Clinical practice. Precocious puberty. N Engl J Med 2008; 358:2366.
- Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009; 123:e752.
- Bar A, Linder B, Sobel EH, et al. Bayley-Pinneau method of height prediction in girls with central precocious puberty: correlation with adult height. J Pediatr 1995; 126:955.
- 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. J Clin Endocrinol Metab 1999; 84:415.
- Fontoura M, Brauner R, Prevot C, Rappaport R. Precocious puberty in girls: early diagnosis of a slowly progressing variant. Arch Dis Child 1989; 64:1170.
- Lazar L, Pertzelan A, Weintrob N, et al. Sexual precocity in boys: accelerated versus slowly progressive puberty gonadotropin-suppressive therapy and final height. J Clin Endocrinol Metab 2001; 86:4127.
- Pasquino AM, Pucarelli I, Segni M, et al. Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone. J Clin Endocrinol Metab 1999; 84:449.
- Lazar L, Padoa A, Phillip M. Growth pattern and final height after cessation of gonadotropin-suppressive therapy in girls with central sexual precocity. J Clin Endocrinol Metab 2007; 92:3483.
- Mul D, Bertelloni S, Carel JC, et al. Effect of gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty: final height results. Horm Res 2002; 58:1.
- Kaplowitz P, Bloch C, Section on Endocrinology, American Academy of Pediatrics. Evaluation and Referral of Children With Signs of Early Puberty. Pediatrics 2016; 137.
- Schoelwer MJ, Donahue KL, Bryk K, et al. Psychological assessment of mothers and their daughters at the time of diagnosis of precocious puberty. Int J Pediatr Endocrinol 2015; 2015:5.
- Kirkham YA, Allen L, Kives S, et al. Trends in menstrual concerns and suppression in adolescents with developmental disabilities. J Adolesc Health 2013; 53:407.
- Fuld K, Chi C, Neely EK. A randomized trial of 1- and 3-month depot leuprolide doses in the treatment of central precocious puberty. J Pediatr 2011; 159:982.
- Lee PA, Klein K, Mauras N, et al. Efficacy and safety of leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of central precocious puberty. J Clin Endocrinol Metab 2012; 97:1572.
- Carel JC, Blumberg J, Seymour C, et al. Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty. Eur J Endocrinol 2006; 154:119.
- Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab 2007; 92:1697.
- Rahhal S, Clarke WL, Kletter GB, et al. Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty. Int J Pediatr Endocrinol 2009; 2009:812517.
- Silverman LA, Neely EK, Kletter GB, 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 2015; 100:2354.
- Lewis KA, Goldyn AK, West KW, Eugster EA. A single histrelin implant is effective for 2 years for treatment of central precocious puberty. J Pediatr 2013; 163:1214.
- Fisher MM, Lemay D, Eugster EA. Resumption of puberty in girls and boys following removal of the histrelin implant. J Pediatr 2014; 164:912.
- Bhatia S, Neely EK, Wilson DM. Serum luteinizing hormone rises within minutes after depot leuprolide injection: implications for monitoring therapy. Pediatrics 2002; 109:E30.
- Demirbilek H, Alikasifoglu A, Gonc NE, et al. Assessment of gonadotrophin suppression in girls treated with GnRH analogue for central precocious puberty; validity of single luteinizing hormone measurement after leuprolide acetate injection. Clin Endocrinol (Oxf) 2012; 76:126.
- Wierman ME, Beardsworth DE, Crawford JD, et al. Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche. J Clin Invest 1986; 77:121.
- Tanaka T, Niimi H, Matsuo N, et al. Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. J Clin Endocrinol Metab 2005; 90:1371.
- Johnson SR, Nolan RC, Grant MT, et al. Sterile abscess formation associated with depot leuprorelin acetate therapy for central precocious puberty. J Paediatr Child Health 2012; 48:E136.
- Davis JS, Alkhoury F, Burnweit C. Surgical and anesthetic considerations in histrelin capsule implantation for the treatment of precocious puberty. J Pediatr Surg 2014; 49:807.
- Chen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. Paediatr Drugs 2015; 17:273.
- Thornton P, Silverman LA, Geffner ME, et al. Review of outcomes after cessation of gonadotropin-releasing hormone agonist treatment of girls with precocious puberty. Pediatr Endocrinol Rev 2014; 11:306.
- Lazar L, Meyerovitch J, de Vries L, et al. Treated and untreated women with idiopathic precocious puberty: long-term follow-up and reproductive outcome between the third and fifth decades. Clin Endocrinol (Oxf) 2014; 80:570.
- Neely EK, Lee PA, Bloch CA, et al. Leuprolide acetate 1-month depot for central precocious puberty: hormonal suppression and recovery. Int J Pediatr Endocrinol 2010; 2010:398639.
- Cassio A, Bal MO, Orsini LF, et al. Reproductive outcome in patients treated and not treated for idiopathic early puberty: long-term results of a randomized trial in adults. J Pediatr 2006; 149:532.
- Palmert MR, Mansfield MJ, Crowley WF Jr, et al. 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; 84:4480.
- Lazar L, Lebenthal Y, Yackobovitch-Gavan M, et al. Treated and untreated women with idiopathic precocious puberty: BMI evolution, metabolic outcome, and general health between third and fifth decades. J Clin Endocrinol Metab 2015; 100:1445.
- Park HK, Lee HS, Ko JH, et al. The effect of gonadotrophin-releasing hormone agonist treatment over 3 years on bone mineral density and body composition in girls with central precocious puberty. Clin Endocrinol (Oxf) 2012; 77:743.
- Pasquino AM, Pucarelli I, Accardo F, et al. Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function. J Clin Endocrinol Metab 2008; 93:190.
- Franceschi R, Gaudino R, Marcolongo A, et al. Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty. Fertil Steril 2010; 93:1185.
- Lee PA, Kerrigan JR. Precocious Puberty. In: Pediatric Endocrinology, Pescovitz OH, Eugster EA. (Eds), Lippincott Williams and Wilkins, Philadelphia 2004. p.329.
- Papanikolaou A, Michala L. Autonomous Ovarian Cysts in Prepubertal Girls. How Aggressive Should We Be? A Review of the Literature. J Pediatr Adolesc Gynecol 2015; 28:292.
- de Sousa G, Wunsch R, Andler W. Precocious pseudopuberty due to autonomous ovarian cysts: a report of ten cases and long-term follow-up. Hormones (Athens) 2008; 7:170.
- Boyce AM, Collins MT. Fibrous Dysplasia/McCune-Albright Syndrome. In: GeneReviews® [Internet], Pagon RA, Adam MP, Ardinger HH, et al. (Eds), University of Washington, Seattle 2015. Available at: http://www.ncbi.nlm.nih.gov/books/NBK274564/ (Accessed on September 18, 2015).
- Holland FJ, Kirsch SE, Selby R. Gonadotropin-independent precocious puberty ("testotoxicosis"): influence of maturational status on response to ketoconazole. J Clin Endocrinol Metab 1987; 64:328.
- Boyce AM, Chong WH, Shawker TH, et al. Characterization and management of testicular pathology in McCune-Albright syndrome. J Clin Endocrinol Metab 2012; 97:E1782.
- Eugster EA. Peripheral precocious puberty: causes and current management. Horm Res 2009; 71 Suppl 1:64.
- Feuillan P, Calis K, Hill S, et al. Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study. J Clin Endocrinol Metab 2007; 92:2100.
- Estrada A, Boyce AM, Brillante BA, et al. Long-term outcomes of letrozole treatment for precocious puberty in girls with McCune-Albright syndrome. Eur J Endocrinol 2016; 175:477.
- Feuillan PP, Foster CM, Pescovitz OH, et al. Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone. N Engl J Med 1986; 315:1115.
- Feuillan PP, Jones J, Cutler GB Jr. Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab 1993; 77:647.
- Nunez SB, Calis K, Cutler GB Jr, et al. Lack of efficacy of fadrozole in treating precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab 2003; 88:5730.
- Shulman DI, Francis GL, Palmert MR, et al. Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development. Pediatrics 2008; 121:e975.
- Mieszczak J, Lowe ES, Plourde P, Eugster EA. The aromatase inhibitor anastrozole is ineffective in the treatment of precocious puberty in girls with McCune-Albright syndrome. J Clin Endocrinol Metab 2008; 93:2751.
- Eugster EA, Rubin SD, Reiter EO, et al. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 2003; 143:60.
- de G Buff Passone C, Kuperman H, Cabral de Menezes-Filho H, et al. Tamoxifen Improves Final Height Prediction in Girls with McCune-Albright Syndrome: A Long Follow-Up. Horm Res Paediatr 2015; 84:184.
- Sims EK, Garnett S, Guzman F, et al. Fulvestrant treatment of precocious puberty in girls with McCune-Albright syndrome. Int J Pediatr Endocrinol 2012; 2012:26.
- Haddad N, Eugster E. An update on the treatment of precocious puberty in McCune-Albright syndrome and testotoxicosis. J Pediatr Endocrinol Metab 2007; 20:653.
- Lumbroso S, Paris F, Sultan C, European Collaborative Study. Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome--a European Collaborative Study. J Clin Endocrinol Metab 2004; 89:2107.
- Lenz AM, Shulman D, Eugster EA, et al. Bicalutamide and third-generation aromatase inhibitors in testotoxicosis. Pediatrics 2010; 126:e728.
- Holland FJ, Fishman L, Bailey JD, Fazekas AT. Ketoconazole in the management of precocious puberty not responsive to LHRH-analogue therapy. N Engl J Med 1985; 312:1023.
- Laue L, Kenigsberg D, Pescovitz OH, et al. Treatment of familial male precocious puberty with spironolactone and testolactone. N Engl J Med 1989; 320:496.
- Leschek EW, Jones J, Barnes KM, et al. Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty onset. J Clin Endocrinol Metab 1999; 84:175.
- Kreher NC, Pescovitz OH, Delameter P, et al. Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole. J Pediatr 2006; 149:416.
- Reiter EO, Mauras N, McCormick K, et al. Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT). J Pediatr Endocrinol Metab 2010; 23:999.
- Soriano-Guillén L, Lahlou N, Chauvet G, et al. Adult height after ketoconazole treatment in patients with familial male-limited precocious puberty. J Clin Endocrinol Metab 2005; 90:147.
- Almeida MQ, Brito VN, Lins TS, et al. Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole. Clin Endocrinol (Oxf) 2008; 69:93.
- US Food and Drug Administration Drug Safety Communication 7/26/13. Nizoral (ketoconazole): Potentially Fatal Liver Injury, Risk of Drug Interactions and Adrenal Gland Problems. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm362672.htm?source=govdelivery (Accessed on July 30, 2013).
- TREATMENT FOR CPP
- Decision to treat
- Goals of treatment
- GnRH agonist therapy
- - Formulations and dosing
- - Monitoring
- - Treatment duration
- - Safety
- - Our approach
- TREATMENT FOR PERIPHERAL PRECOCITY
- General approach
- McCune-Albright syndrome
- - Girls
- - Boys
- Familial male-limited precocious puberty
- BENIGN OR NON-PROGRESSIVE PUBERTAL VARIANTS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS