Abstract
1. What is precocious puberty?
Precocious puberty is defined as the onset of secondary sexual characteristics before the age of 8 years in girls (Tirumuru et al., 2012). There is often an overlap between the terms adolescence and puberty. The former refers mainly to the social and the psychological changes, while the latter incorporates the physical signs.
Observational studies have reported that more girls are beginning to experience normal pubertal changes before the age of 8 and that this varies with ethnicity (Cisternino et al., 2000). Dietary and environmental factors may also affect the age of puberty (Chen et al., 2018). This has led to a call for a change in the age limit for defining normal puberty, but this is currently a matter of debate.
A potential danger of lowering the age of puberty is the likelihood of missing serious pathology (Cisternino et al., 2000). Some of the studies are several years old and to ensure safe practice, use of the same 8 year age cut-off for evaluating precocious puberty in girls is recommended.
2. What is the relevance?
Precocious puberty can be a sign of secondary diseases, such as central nervous system abnormalities or rapidly progressing ovarian tumours. A potential imbalance between the patient’s physically mature appearance and chronological age has a psychological impact on the patient and their family. Affected children may present initially with tall stature for their age and accelerated bone maturation. However, their final adult height may be compromised by premature epiphyseal fusion. These children are also at increased risk of sexual abuse and early pregnancy (Herman-Giddens et al., 1988).
3. What is normal puberty?
Puberty is a period of transition between childhood and adult life when growth accelerates and secondary sexual characteristics develop. It is the process of physical change that ultimately allows for sexual reproduction. The endocrinological onset of puberty begins several years before physical changes are visible. During childhood, the hypothalamo–pituitary–ovarian (HPO) axis remains quiescent. Between the ages of 7 and 9 years, the Gonadotropin releasing hormone (GnRH) secretory system becomes activated, stimulating the pituitary gland to produce follicle stimulating hormone (FSH) and luteinising hormone (LH). They act on the ovaries leading to a rise in circulating oestrogen levels. Initially, oestrogen acts upon the breast tissue to cause thelarche (development of breast tissue) followed by adrenarche (rise in secretion of androgens), which leads to pubarche (development of pubic hair). Menarche (onset of menstrual periods) usually occurs 2–3 years after thelarche.
4. What are the types of precocious puberty?
Precocious puberty is classified into central precocious puberty (CPP) or peripheral precocious puberty (PPP). CPP or true precocious puberty is always isosexual (where the secondary sexual characteristics are appropriate for the child's sex), whereas PPP can be isosexual or heterosexual (where the secondary sexual characteristics are contrary to the phenotypic sex, such as the appearance of male physical characteristics, known as virilisation in girls).
There is also a third category known as benign precocious puberty. Children affected in this category have precocious development involving only one secondary sexual feature, such as premature thelarche, pubarche or menarche. It is considered to be a benign condition provided other potential causes are excluded.
5. What are the causes of CPP?
The majority of cases of CPP are idiopathic in nature and occur owing to premature activation of the HPO axis. CPP follows the usual clinical course of normal pubertal development. CPP can be secondary to central nervous system pathology, including congenital abnormalities, acquired conditions (such as tumours, trauma and infection) or following chemotherapy. It can also occur in children with hypothyroidism owing to stimulation of the FSH receptors by high levels of thyroid stimulating hormone (TSH).
6. What are the causes of PPP?
PPP results from the secretion of sex steroids, which is autonomous and independent of the HPO axis. It could be secondary to:
Exogenous sex hormones McCune–Albright Syndrome (characterised by polyostotic fibrous dysplasia or abnormal bone cysts, café au lait spots) Adrenal causes: Congenital adrenal hyperplasia, neoplasm or Cushings Syndrome Ovarian causes: Oestrogen secreting tumours (granulosa cell tumours) or androgen secreting tumours (Sertoli–Leydig cell tumours) or functioning ovarian follicular cysts.
Unlike CPP, in PPP the sequence of pubertal events may be disordered and may vary dependant on the cause. Girls with McCune–Albright syndrome tend to present with premature menarche as the first clinical sign. Granulosa cell tumours often present with premature breast development or vaginal bleeding, while androgen-producing ovarian tumours present with progressive virilisation. Virilisation is characterised by symptoms of hirsutism with deepening of voice, clitoromegaly, temporal hair recession, breast atrophy or increase in muscle mass.
7. How is a child with precocious puberty evaluated?
Assessment of precocious puberty.
NB: These are organised in secondary care, however some may be considered in primary care without delaying the referral.
8. What are the treatment options available?
The main aim of management is to identify and treat any life-threatening conditions, and to regress the physical changes of puberty. This will reduce the psychological impact of accelerated physical age and maximise the final height, which is typically predicted to be shortened owing to early epiphyseal closure (Lee and Houk, 2006). The decision on treatment should be multidisciplinary, taking into consideration the underlying cause, the extent of the pubertal change and the wishes of the child and parent. Gonadotrophin-releasing hormone analogues (GnRHa) are the mainstay of treatment for CPP. The agents used are agonists that act by down regulating GnRH receptors and pituitary desensitisation, leading to reduced gonadotrophin synthesis. Initially a transient withdrawal bleed may occur, secondary to the initial production of a sudden release of gonadotrophins, known as a flare.
GnRHa are available as rapid-acting or long-term depot preparations and can be administered subcutaneously or intramuscularly every 3–4 weeks or as a long-acting depot at 10 to 12-weekly intervals. In some cases, addition of a growth hormone may be required as GnRHa may result in a drastic slowing of the growth rate. The height gained is variable and therefore each child should be individually assessed for dose and duration of growth hormone. Treatment is usually stopped when it is appropriate for normal puberty to begin. Monitoring of treatment is carried out through anthropometric measurement, assessment of pubertal progression, bone age and LH response to GnRHa stimulation (reduced LH level indicates a good response to treatment).
Side effects of treatment include headaches, hot flushes, mood swings, injection site reactions and weight gain. The suppression of puberty is reversible on cessation of treatment and there is no long-term impact on adult fertility and bone age (Lee and Houk, 2006).
In cases of PPP, additional treatment may be required to address the specific cause, such as surgical excision of an ovarian tumour with or without adjuvant chemotherapy/radiotherapy.
9. Prognosis
Long-term prognosis depends on the cause, especially in PPP, and CPP secondary to central nervous system (CNS) causes. These children are not at a risk of premature menopause or osteoporosis.