Recent Trends in Pubertal Timing and Current Management of Precocious Puberty in Girls

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Precocious puberty is defined as the development of pubertal signs at a younger age than the accepted lower limits for the onset of puberty. In girls, breast development before the age of 8 years, appearance of sexual pubic hair before the age of 8 years or beginning menses before the age of 9.5 years is traditionally considered as precocious puberty. This is accompanied by rapid growth rate, advanced skeletal maturation and increased levels of gonadotropins and/or sex steroids.

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Recent Trends in Pubertal Timing and Current Management of Precocious Puberty in Girls

  1. 1. Recent Trends in Pubertal Timing and Current Management of Precocious Puberty in Girls.
  2. 2. Review Article Recent trends in pubertal timing and current management of precocious puberty in girls Anjana Hulse* Consultant Pediatric Endocrinologist, Apollo Hospitals, Bangalore, India a r t i c l e i n f o Article history: Received 28 April 2013 Accepted 15 May 2013 Available online 6 June 2013 Keywords: Precocious puberty GnRHa therapy Early puberty a b s t r a c t Precocious puberty is defined as development of pubertal signs at a younger age than the accepted lower limits for the onset of puberty. Precocious puberty can be classified as gonadotropin dependent (central or true) and gonadotropin independent (peripheral or pseudo). Commonest etiology in girls is idiopathic gonadotropin dependent precocious puberty. Recently, timing of onset of puberty in girls has gained considerable interest among the professionals and general public. Recent data suggests a decrease in the age of onset of puberty in girls over the past 2e3 decades which may be attributable to increased incidence of obesity, improved nutrition and other environmental factors. Precocious puberty in girls warrants prompt evaluation and early initiation of treatment to optimize adult height potential and to minimize psychosocial stress to the child. Treatment is directed at the primary cause. Gonadotropin releasing hormone analog (GnRHa) is the treatment of choice for gonadotropin dependent precocious puberty. GnRHa are effective in preventing pubertal progression clinically as well as biochemically. A va- riety of GnRHa preparations are available and the details are mentioned in the text. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction Precocious puberty is defined as the development of pubertal signs at a younger age than the accepted lower limits for the onset of puberty. In girls, breast development before the age of 8 years, appearance of sexual pubic hair before the age of 8 years or beginning menses before the age of 9.5 years is traditionally considered as precocious puberty. This is accompanied by rapid growth rate, advanced skeletal matu- ration and increased levels of gonadotropins and/or sex steroids. Precocious puberty can be classified as gonadotropin dependent (central or true) and gonadotropin independent (peripheral or pseudo). Central precocious puberty (CPP) is due to premature activation of hypothalamoepituitaryegonadal (HPG) axis. There is no activation of HPG axis in peripheral precocious puberty (PPP). Even though organic lesions of the central nervous system (CNS) are occasionally the cause of precocious puberty, in the vast majority of the girls, CPP is idiopathic. The source of sex steroid in PPP is endogenous as in ovarian cysts or tumors; or adrenal as in adrenal tumors or CAH; or exogenous such as ingestion of estrogen containing * TF3, Dhanush Paradise, 10th Cross, 5th Main, Vijaya Bank Layout, Behind IIM-B, Bangalore 76, India. Tel.: þ91 (0) 80 26304050, þ91 (0) 9591382502 (mobile). E-mail address: anmhulse@gmail.com. Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 3 4 e1 3 7 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.05.010
  3. 3. pills or other endocrine disruptors (ED) present in food or cosmetics. 2. Recent trends in pubertal timing CPP is 10 times (female to male ratio varies from 3:1 to 23:1) more common in girls than in boys.1,2 During the past 2e3 decades the timing of onset of puberty in girls has been a topic of debate among pediatric endocrinologists. European data have shown a sharp decline in age at menarche from 17 years in the early 19th century to about 13 years in mid 20th cen- tury.3 In the past 25 years a decrement of 2.5e4 months in age at menarche has been noticed in both Europe and United States.4e6 In contrast to menarche, age at onset of breast development seem to have declined markedly from a mean age of 11 years to less than 10 years during the past 2 decades.7 Although these findings were reported by two American studies in 1990s similar findings were confirmed in Europe 15 years later.4,7,8 These studies prompted (LWPES) to recom- mend a lower age limit for evaluation of precocious puberty in girls from 8 years to 7 years.9 These recommendations were based mainly on Pediatric Research in Office Settings network (PROS)/National Health and Nutrition Examination Survey (NHANES III) study where only girls up to the age of 12 years were included. Moreover, NHANES study mainly relied on vi- sual grading of breast development which may not be the appropriate way to assess puberty in obese individuals. The proposal of lowering of the age for evaluation of precocious puberty in girls by LWPES was criticized by many experts. More recently Copenhagen Puberty Study reported 12 months decline in mean age at onset of puberty in Danish girls.4 Further studies clearly suggest a secular trend toward earlier onset of breast development where as age at menarche has changed only marginally. However, extrapolation from these cross sectional findings may not be appropriate to redefine the age limit for evaluation of precocious puberty and may lead to possible misdiagnosis of potentially treatable underlying pa- thology in about 5e10% girls.10 Therefore, cut off values for age at which diagnostic evaluation is needed should not be lowered. Rapid change in pubertal timing in the recent years is a pointer toward environmental influence on puberty in chil- dren. Recent increase in the incidence of childhood obesity has also contributed to early onset of puberty in girls. Genetic factors, fetal nutrition and physical activity also play a role. Catch up growth following early fetal or post natal under nutrition may also be associated with early puberty.11 3. Evaluation of precocious puberty in girls More than 90% of the girls with precocious puberty have gonadotropin releasing hormone (GnRH) dependent preco- cious puberty. Diagnostic evaluation is based on the devel- opment of physical pubertal changes and laboratory testing that are consistent with progressive changes of HPG axis activation. Documentation of history, physical examination findings and assessing hormonal status make important part of evaluation. History taking should include growth patterns since birth, age of onset of physical changes, past medical, family and psychosocial history. Possibility of exposure to exogenous hormones should be explored. Past history of CNS infection, tumors, chemo or radiotherapy should be elicited. Gelastic seizures may occur with CNS hamartomas. Physical examination should include careful assessment of growth, growth velocity, BMI, Tanner staging and systemic examina- tion including fundus examination. Visualization of vaginal mucosa to look for the evidence of estrogenization should be included as a part of the examination. Initial hormonal evaluation should include assessment of bone age hormonal assays including luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2) and where indicated dehydroepiandrostenedione (DHEAS) and thyroid function tests. LH measurements are most valuable for diagnosing precocious puberty. Pre-pubertal LH levels are less than 0.1 IU/L. Basal LH level greater than 0.2 IU/L may have 100% sensitivity and specificity for boys, but there 50% of the girls in Tanner stage II breast development may have pre- pubertal LH levels.12 Because of the variations in basal levels and overlap between pre-pubertal and early pubertal hor- monal levels, GnRH/GnRHa stimulation test is considered as the gold standard to confirm the diagnosis of GnRH dependent precocious puberty. However, there is a lot of debate about the cut off values of LH and FSH for diagnosis of puberty following stimulation with GnRH/GnRHa. Moreover, GnRH stimulation test has low sensitivity, though it is highly specific for con- firming precocious puberty.13 Conventionally, a peak LH value more than 4.2e5 IU/L or a greater stimulated peak of LH/FSH is considered as pubertal response. Peak levels of gonadotropins are obtained 30 min after GnRH stimulation and 60 min after GnRHa such as Leuprolide injection.14 Sensitive assays with pediatric norms should be used. Pelvic ultrasound in girls determines the ovarian and uterine size. Uterine length, transverse diameter, endometrial thickness, ratio of fundus to cervix, ovarian size and volume, number of follicles and size of the biggest follicle should be measured. Cut off values for uterine length is considered to be about 4 cm and fundus to cervix ratio of more than 2:1 is suggestive of pubertal status. Presence of endometrial echo is highly specific but less sensitive.15 Cut off for pubertal ovarian volume is about 1e3 ml.16 MRI of the CNS is usually done to identify CNS lesions, though this investigation can be omitted in older girls presenting with typical features of true central precocious puberty. 4. Treatment Early treatment of precocious puberty is utmost important. If untreated, precocious puberty may lead to early epiphyseal fusion and compromised final height.17,18 In addition early puberty/menarche can cause significant psychological stress in young girls.19 Treatment of precocious puberty is directed at the primary cause. GnRHa is the treatment of choice for GnRH dependent precocious puberty. GnRHa suppresses the episodic secretion of gonadotropins by continued occupation of the GnRH re- ceptors on the pituitary gonadotropes with high level of GnRHa. Girls with onset of progressive central precocious a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 3 4 e1 3 7 135
  4. 4. puberty before the age of 6 years benefit the most in terms of height from GnRHa therapy. A variety of GnRHa formulations are available (monthly and depot preparations for intramus- cular use; intranasal and sub-cutaneous injections). Commonly used GnRHa include Goserelin, Buserelin, Leu- prolide, Triptorelin and Histrelin. GnRHa are expensive and this may be a limiting factor for its use for patients from lower socioeconomic status in developing countries. For most chil- dren, monthly injections in a dose of 0.3 mg/kg/28 days adequately suppress the gonadotropins. Occasionally more frequent injections may be required. Depot preparations (3 monthly) also have been tried and shown to be equally effi- cacious and is useful when compliance in an issue.20 But larger randomized trials are required to confirm the effec- tiveness and safety of depot preparations. The choice of therapy depends on local availability, physician as well as patient or parents’ choice. GnRHa are generally well tolerated. Hot flushes, headaches and sterile abscess have been described in the literature but the incidence is very low. Anaphylaxis is extremely rare. Vaginal bleeding may occur after the first injection but, should cease with subsequent doses. Some pediatric endocrinologists suggest measurement of stimulated LH and E 2 levels to assess the efficacy of treatment. However there is no consensus on routine use of this. Decline in growth velocity and bone age advancement should occur during treatment. Progression of breast devel- opment or other pubertal signs (not pubic hair) suggests fail- ure of treatment and calls for re-evaluation of the patient. Discontinuation of GnRHa at a chronological age of 11 years and at a bone age of 12 years has been associated with maximum adult height.21 Timing of cessation of therapy de- pends on the parents’ and the child’s wish and also physi- cian’s assessment. In one study menses began at a mean of 16 months after stopping the treatment with GnRHa.21 Currently available data does not suggest impairment of gonadal func- tion in long term after stopping GnRHa therapy.21 Weight gain and reduction in bone mineral density in children treated with GnRHa have been mentioned, but these findings are not objectively supported by the studies.21 GnRHa therapy is also used for hypothalamic hamartoma. Treatment of PPP is directed against the cause and could be sometimes challenging. CNS tumors, ectopic gonadotropin producing gonadal and adrenal tumors require surgery, radio or chemotherapy. Adrenal suppression in CAH and thyroxine replacement in hypothyroidism is required. Where there is autonomous gonadal steroid suppression such as McCune- eAlbright syndrome aromatase inhibitors or ketoconazole have been used to reduce the effect of sex steroids. 5. Newer therapies Histrelin implant has been tried in girls with CPP in some centers. There was no difference in terms of final height achievement in children treated with implant or long acting GnRHa. Menarche occurred sooner after removal of the implant.22e25 However, long term studies are still awaited. Orally acting GnRHa are also under development and poten- tially could be used to treat children with central precocious puberty in future. Adjunctive therapy with growth hormone or oxandrolone have been tried, but are not routinely advo- cated yet. 6. Conclusion Population based studies have shown a shift towards earlier mean age at the onset of breast development in girls in the past two to three decades. These studies have not confirmed rapid progression of entire sequence of puberty including menarche. Even then, to avoid overlooking a small subset of children with rapidly progressive puberty and to avoid missing the pathological causes of puberty, lowering the normal age for the evaluation of precocious puberty is not advisable. Treatment with GnRHa is reversible, safe and effective for CPP in girls. Treatment of PPP sometimes is challenging. Long term studies looking at the use of depot GnRHa preparations for CPP and newer routes of administration such as implants are needed. Cost of the treatment is also a limiting factor for use of GnRHa for treatment of precocious puberty in devel- oping countries like India. Conflicts of interest The author has none to declare. r e f e r e n c e s 1. Teilmann G, Pedersen CB, Jensen TK, Skakkebaek NE, Juul A. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Pediatrics. 2005;116:1323e1328. 2. Berberoglu M. Precocious puberty and normal variant puberty: definition, etiology, diagnosis and current management. J Clin Res Pediatr Endocrinol. 2009;1:164e174. 3. Tanner JM. Trend towards earlier menarche in London, Oslo, Copenhagen, the Netherlands and Hungary. Nature. 1973;243:95e96. 4. Aksglaede L, Sorensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics. 2009;123:e932ee939. 5. Rubin C, Maisonet M, Kieszak S, et al. Timing of maturation and predictors of menarche in girls enrolled in a contemporary British cohort. Paediatr Perinat Epidemiol. 2009;23:492e504. 6. Anderson SE, Dallal GE, Must A. Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart. Pediatrics. 2003;111:844e850. 7. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings Network. Pediatrics. 1997;99:505e512. 8. Karpati AM, Rubin CH, Kieszak SM, Marcus M, Troiano RP. Stature and pubertal stage assessment in American boys: the 1988e1994 Third National Health and Nutrition Examination Survey. J Adolesc Health. 2002;30:205e212. 9. Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Drug and a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 3 4 e1 3 7136
  5. 5. Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999;104:936e941. 10. Sorensen K, Mouritsen A, Aksglaede L, Hagen CP, Mogensen SS, Juul A. Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty. Horm Res Paediatr. 2012;77(3):137e145. 11. Proos L, Gustafsson J. Is early puberty triggered by catch-up growth following undernutrition? Int J Environ Res Public Health. 2012 May;9(5):1791e1809. 12. Resende EA, Lara BH, Reis JD, Ferreira BP, Pereira GA, Borges MF. Assessment of basal and gonadotropin-releasing hormone-stimulated gonadotropins by immunochemiluminometric and immunofluorometric assays in normal children. J Clin Endocrinol Metab. 2007;92(4):1424e1429. 13. Kılıc¸ A, Durmus‚ MS, Unuvar E, et al. Clinical and laboratory characteristics of children referred for early puberty: preponderance in 7e8 years of age. J Clin Res Pediatr Endocrinol. 2012 December;4(4):208e212. 14. Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler Jr GB. Premature thelarche and central precocious puberty: the relationship between clinical presentation and the gonadotropin response to luteinizing hormone-releasing hormone. J Clin Endocrinol Metab. 1988;67:474e479. 15. de Vries L, Horev G, Schwartz M, Phillip M. Ultrasonographic and clinical parameters for early differentiation between precocious puberty and premature thelarche. Eur J Endocrinol. 2006;154(6):891e898. 16. Battaglia C, Mancini F, Regnani G, Persico N, Iughetti L, De Aloysio D. Pelvic ultrasound and color Doppler findings in different isosexual precocities. Ultrasound Obstet Gynecol. 2003;22(3):277e283. 17. Kauli R, Galatzer A, Kornreich L, Lazar L, Pertzelan A, Laron Z. Final height of girls with central precocious puberty, untreated versus treated with cyproterone acetate or GnRH analogue. A comparative study with re-evaluation of predictions by the BayleyePinneau method. Horm Res. 1997;47:54e61. 18. Brauner R, Adan L, Maiandry A, Zantleifer D. Adult height in girls with idiopathic true precocious puberty. J Clin Endocrinol Metab. 1994;79:415e420. 19. Ehrhardt AA, Meyer-Bahlburg HFL. Idiopathic precocious puberty in girls: long-term effects on adolescent behavior. Acta Endocrinol Suppl (Copenh). 1986;279:247e253. 20. Badaru A, Wilson DM, Bachrach LK, et al. Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab. 2006;91(5):1862e1867. 21. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics. 2009;123:e752. 22. 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(5):1697e1704. 23. Hirsch HJ, Gillis D, Strich D, et al. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics. 2005;116(6). 24. Gillis D, Karavani G, Hirsch HJ, Strich D. Time to menarche and final height after histrelin implant treatment for central precocious puberty. J Pediatr 2013 Feb 26; http://dx.doi.org/ 10.1016/j.jpeds.2013.01.021. pii: S0022e3476(13)00045-0. [Epub ahead of print]. 25. Kappy MS, Ganong CS. Advances in the treatment of precocious puberty. Adv Pediatr. 1994;41:223e261. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 3 4 e1 3 7 137
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