Causes, diagnosis, and treatment of central precocious puberty

Summary

Central precocious puberty results from the premature activation of the hypothalamic-pituitary-gonadal axis. It mimics physiological pubertal development, although at an inappropriate chronological age (before 8 years in girls and 9 years in boys). It can be attributable to cerebral congenital malformations or acquired insults, but the cause in most cases in girls remains unknown. MKRN3 gene defects have been identified in familial disease, with important basic and clinical results. Indeed, genetic analysis of this gene should be included in the routine clinical investigation of familial and idiopathic cases of central precocious puberty. Gonadotropin-releasing hormone agonists are the gold-standard treatment. The assessment and management of this disease remain challenging for paediatric endocrinologists. In this Series paper, we describe current challenges involving the precise diagnosis and adequate treatment of this disorder.

Introduction

Puberty represents a complex biological process of sexual development that can be affected by genetic, nutritional, environmental, and socioeconomic factors. During this phase of development, individuals attain secondary sexual characteristics and reproductive capacity. In girls, the onset of puberty is defined clinically as the first appearance of breast buds, whereas in boys, testicular enlargement is the first pubertal sign.¹ In both sexes, pubic hair appearance can begin before, together with, or after the clinical onset of puberty.¹

The normal age range for puberty onset refers to the time in which 95% of children attain initial pubertal signs (Tanner and Marshall stage 2 in both sexes).2, 3 In the 1960s, cross-sectional data led to designation of the normal age range of pubertal onset between ages 8 and 13 years in girls and between ages 9 and 14 years in boys. In the past two decades, cross-sectional data from the USA and Europe suggests that pubertal milestones are being reached earlier than previously thought in both sexes.4, 5, 6, 7 The putative decrease in age at the start of puberty has largely been attributed to improved health, nutrition, and sanitation.⁸

These findings guided recommendations to classify pubertal development as precocious when it occurs before age 6 years in black girls and before age 7 years in all other girls.⁴ However, the validity of these initial recommendations was questioned because the Tanner staging of breast development was established mainly by inspection and not palpation.³ In 2009, Roelants and colleagues⁶ updated the reference charts for pubertal development in a large group of healthy Belgian children. The median age at menarche (13·0 years) had not advanced over the previous 50 years, despite the increasing prevalence of overweight and obesity in children older than 5 years in this period. However, about 10% of girls and boys in the study had initial pubertal development before age 9 years. In 2013, Biro and colleagues⁷ reported that the onset of thelarche at younger ages is associated with ethnic origin and temporal changes in BMI, confirming and extending patterns seen in previous studies.4, 5, 6, 7, 8 The lower age at thelarche in girls did not seem to be caused by gonadotropin-releasing hormone (GnRH) activation—but other potential mechanisms, such as endocrine disruptors and nutritional effects, might have had a role in this process.⁹

The most common mechanism of precocious puberty is the early activation of pulsatile GnRH secretion, known as gonadotropin-dependent precocious puberty or central precocious puberty. The estimated incidence in American girls is 1 in 5000–10 000.¹⁰ However, the prevalence was 1 in 500 among Danish girls, based on national registries over a 9-year period (1993–2001).¹¹ The prevalence is sexually dimorphic, being higher in girls than in boys (15–20 girls for every boy).

The timing of puberty has substantial biological, psychosocial, and long-term health implications.1, 12 Concerns are associated with the diagnosis of precocious puberty, such as early menarche in girls, short adult stature because of early epiphyseal fusion, and adverse psychosocial outcomes. Evidence suggests an association between early timing of puberty and adverse health outcomes in later life.8, 12, 13 Early age at menarche has been associated with increased risks of obesity, hypertension, type 2 diabetes, ischaemic heart disease, stroke, oestrogen-dependent cancer, and cardiovascular mortality.12, 13 Additionally, early age at menarche is a known risk factor for the development of breast cancer.14, 15 This association is largely attributed to high early exposure to oestrogen during the initial stages of breast development and throughout the reproductive years. Some evidence suggests that children with precocious puberty have increased sexual and delinquent behaviours in adulthood, or more psychological disturbances over and above general trends reported in children who undergo a normal puberty.16, 17 In this Series paper, we describe the known and new causes of central precocious puberty. We focus on the clinical assessment of central precocious puberty, and outline the challenges involved in the precise diagnosis and management of this common paediatric disorder.