Approach
The main aims of treatment, in the short term, are to prevent progression of secondary sexual characteristics, and of menarche in girls. The long-term aim is to maximize the growth potential and psychosocial well-being. The underlying cause, if any, must be treated. Not all children need treatment, as puberty may progress slowly. Children should be monitored for progression of pubertal development and growth velocity for 6 months before a decision to treat is made. The initiation of investigations may need to be considered depending on the individual circumstances such as age, puberty stage, and rate of progression. Patients should be referred to a pediatric endocrinologist for evaluation and treatment.
The decision regarding commencing treatment is based on several factors, such as age at onset, predicted adult height, psychological effects, and rate of progression of puberty. The younger and shorter the patient at onset, the more compromised will be adult height.
Treatment will halt progress of the disease, but regression of certain already established secondary sexual characteristics is only minimal. Breast development is arrested and can regress significantly. Menarche, if already established, will be halted. Parents of girls with learning disability often request treatment, anxious that their daughter will not understand or be able to cope with menstruation.
Central precocious puberty (CPP) is typically treated with a gonadotropin-releasing hormone agonist (GnRH agonist). Treatment of gonadotropin-independent precocious puberty (GIPP) is not straightforward; it includes the use of agents to inhibit steroidogenesis and reduce estrogen formation, which is a prime driver of bone maturation acceleration.
Central precocious puberty (CPP)
In the majority of females with CPP, no apparent cause is found. However, in many boys an underlying etiology is contributory, and this should be identified and treated. This includes:
Referral and optimal management of any associated brain neoplasms (e.g., optic nerve gliomas); other hypothalamo-pituitary tumors; hamartomas; and neurodisability conditions such as hydrocephalus.[27][28]
Patients who have developed CPP as a consequence of cranial radiation should continue to be monitored for tumor recurrence and any other pituitary hormone deficiencies.
Very rarely, midline forebrain defects may be accompanied by CPP and other pituitary hormone abnormalities.[34] These patients should be monitored for evolving hormone deficiencies.
Sexual abuse has been reported as a precipitating cause of CPP.[37] Early pubertal development in these patients can regress with a change in environment.
Gonadotropin-releasing hormone (GnRH) agonists
Continuous exposure of the GnRH receptor to GnRH suppresses puberty, as it is only the pulsatile exposure that triggers pubertal progression. Synthetic preparations of GnRH agonists are available with a longer half-life than natural GnRH and are used successfully in the treatment of CPP. GnRH agonists are the only effective treatment modality for CPP.
GnRH agonists have the paradoxical effect of down-regulating gondadotropin release when administered in depot form at a high dose. Intranasal preparations have also been used previously, but are now rendered obsolete by the depot preparations.
Recommended GnRH agonists include leuprolide, triptorelin, or goserelin depot preparations.[58] An implantable GnRH agonist, histrelin, has been used successfully. The implant is effective for at least a year, possibly more.[59][60][61]
Treatment improves the adult height to a degree with rapidly progressing puberty, based on a calculation of a predicted adult height, particularly in younger children (<6 years old).[62][63][64][65][66] There is only minimally convincing evidence of an improvement in adult height with GnRH agonist treatment after the bone age of 12.5 years in girls and 14 years in boys.[66] Therefore, for children with more advanced bone age at presentation, parents need to be told that treatment may have little effect on adult height, and an informed discussion of costs and benefits is needed prior to recommending therapy.[67] There are few results of adult height benefit in boys. A difficulty with the under 6 years of age data is that height prediction at that age is associated with large errors, reducing the likelihood that any effect is real.
Suppression of puberty with these agents is reversible with few adverse effects. Withdrawal of sex steroids following initial treatment can result in uterine bleeding in girls. It can also result in menopausal symptoms such as mood swings and hot flashes. Bone mineral density and future reproductive function do not appear to be affected.[66]
Treatment should be stopped once an acceptable age of puberty is reached. The decision to discontinue therapy should be individualized and the chronologic age, bone age, growth velocity, and desires of the patient and family should be taken into consideration. Gonadotropin secretion recommences approximately 3 to 4 months after stopping of treatment, with normal pubertal progress, menses within 6 months to 2 years, and fertility.
Growth hormone (GH)
Treatment with GnRH agonists can lead to a reduction in the growth rate due to a reduction in GH and insulin-like growth factor 1 (IGF1) concentrations.
Addition of GH treatment to GnRH agonist therapy may lead to a better growth velocity, although data on an improved adult height are not convincing.
Gonadotropin-independent precocious puberty (GIPP)
Treatment of GIPP is more complicated. Optimum management of disorders such as congenital adrenal hyperplasia (CAH) with hydrocortisone (with or without fludrocortisone) therapy will help prevent rapid virilization in patients with GIPP due to CAH. Typically, they do not need any further drug treatment unless they have developed secondary CPP. Tumors of the ovary, testes, or adrenals need surgery. Human chorionic gonadotropin tumors are more difficult to treat and patients may need a combination of surgery, chemotherapy, and radiation. Identification of exogenous estrogens or androgens as the cause of GIPP should lead to a prompt discontinuation of the drugs.
Children with McCune-Albright syndrome (MAS) and testotoxicosis (familial male limited GIPP) need pharmacotherapy to prevent the synthesis or action of gonadal steroids. Pharmacotherapeutic options include ketoconazole, aromatase inhibitors (e.g., letrozole, anastrozole), and antiandrogen agents (e.g., spironolactone, bicalutamide).[68][69][70][71][72][73][74] These therapies should only be considered in specialist settings.
Ketoconazole acts as an inhibitor of steroid synthesis and suppresses both gonadal and adrenal steroid production. It helps decrease testosterone levels and achieve good growth. Ketoconazole may cause severe liver injury and adrenal insufficiency. Its use requires expert guidance and it is contraindicated in patients with liver disease. If used, liver and adrenal function should be monitored before and during treatment.[75]
Aromatase inhibitors (e.g., anastrozole, letrozole) reduce growth rate and bone age advance. If used, antiandrogen agents may be required to reduce testosterone effects on pubic hair and genital development. These include spironolactone and bicalutamide.[71]
Patients with MAS also have hyperfunctioning of other endocrine glands, such as hyperthyroidism and Cushing disease, and they need appropriate management. Medroxyprogesterone may be used to stop vaginal bleeding in females with MAS, but it does not halt the progression of bone age or bony lesions.[76] Tamoxifen, an antiestrogen, has also been used to reduce vaginal bleeding.[77] Laparoscopic cystectomy of ovarian cysts may be required in severe disease.
Prolonged sex-steroid exposure in MAS, testotoxicosis, or CAH may have a direct maturational effect on the hypothalamus and can accelerate the onset of centrally mediated puberty, thus leading to secondary CPP. If this occurs, adjunctive GnRH agonist therapy is indicated.
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