CM Yu

Puberty is defined as the period of maturation with the development of secondary sexual characteristics and the acquisition of reproductive capability. The associated physical and psychological changes are results of increase in sex hormone secretion. Onset of puberty is heralded by a pulsatile sleep-entrained luteinising hormone(LH) secretion which is reflective of the episodic release of luteinising hormone releasing hormone (LHRH) from the hypothalamus (Fig. 1).

Fig. 1

The first sign of puberty in female is breast enlargement and in male, the testicular enlargement. The normal sequence of pubertal development was firstly described by Marshall and Tanner.^1,2 Precocious puberty is said to occur when the onset of puberty is earlier than expected, the normal age limits being defined by general population study. Precocious puberty can be classified as luteinising hormone releasing hormone dependent (central or true) or LHRH independent (pseudo).

Establishment of normality in puberty should take into consideration of the ethnic, geographical and social differences. In general, puberty occurs earlier in tropical and well developed countries. Most western countries experienced earlier onset of puberty since the late nineteenth century probably related to the improvement in social economical condition and nutrition. In Hong Kong, the mean age of onset of puberty has changed from 11 years in 1963 to 10 years in 1993 in girls³ and from 13 years to 11.5 years in boys.⁴ From the 1993 survey, the onset of puberty before 7 years in girl and 8 years in boy is considered premature. However, most of these children represent one end of the normal bell-shaped distribution curve of pubertal timing and may not necessary be pathological. Out of these children, some will have associated early growth spurt and impaired adult height, increased prevalence of emotional disturbance which may be benefited from treatment. Further investigation is needed to define these children.

Because of the pulsatile nature of hormonal secretion, random sampling of blood for gonadotrophins or sex hormone is of no little value in the diagnosis of pubertal disorders. In central precocious puberty, an intravenous LHRH injection (100 ug ) is characterized by predominant rise of LH at 30 or 60 minutes. The peak LH is every higher in precocious pubertal state than in normal pubertal state (Fig. 2). X ray of left wrist will demonstrate a significant bone age advancement compared with chronological age. Ultrasound assessment of pelvis in girls will show presence of endometrial echo, enlargement of uterus of more than 4 cm fundal cervical ratio greater than one, and ovarian volume greater than 2 ml with multicystic appearance. It is understood that ultrasound changes in the presence of clinical evidence of early pubertal development makes the diagnosis of precocious puberty very likely but a completely normal pelvic ultrasound does not exclude the diagnosis and serial examinations are needed. MRI or CT scan of brain is indicated to exclude intracranial pathology especially in boys. However, majority of girls have idiopathic precocious puberty and extensive investigation is probably unnecessary.

Fig. 2

Treatment aims to stop pubertal progression, relieve the associated emotional disturbance and anxiety and attain normal genetic height potential. Previously oral progestogens such as medroxyprogesterone acetate (Provera) or cyproterone acetate (Androcur) were used for control of precocious puberty. These drugs are largely obsolete because of their disappointing effect on height prognosis and the general availability of LHRH agonists (LHRHa).

LHRHa is the synthetic analogue of natural LHRH decapeptide molecule resulting in 20-150 fold increase in potency. Binding of LHRHa molecules to the LHRH receptor will cause an initial stimulation rapidly follow by down regulation of the receptor and inhibit gonadotrophin secretion. There are different preparations of LHRHa available in the market. They can be administered either intranasally 4-6 times daily, daily subcutaneous injection, or as monthly intramuscularly depot injection. The long acting monthly depot preparation is most commonly used because of its better bioavailability and compliance. Biochemical response can be demonstrated after three months, regression of secondary sexual characteristics in six months, skeletal advancement and reduction of height velocity gradually after one year of treatment and eventually to pharmacological gonadectomy. Psychological disturbance associated with early sexual development also seems to improve with treatment.

The final adult height for untreated patients were significantly reduced when compared to the mid - parental height or the general population. While suppression of sex steroid secretion is usually effective, some authors were cautious about the benefit of LHRHa treatment in attaining the optimal final adult height.⁵ In 1993, Cutler et al⁶ reported the NIH study on 38 girls with precocious puberty treated with LHRHa for 4 years, the final height increased from - 2.0 SDS to - 1.0 SDS, even though their average age of onset of treatment was 7.2 years with delayed of 3.1 years after presentation. Paul and Grumbach et al⁷ reported 20 girls treated with LHRHa for 5.7 years who have achieved near final height of -1 SDS compared to untreated control of - 2.4 SDS. Furthermore, because of the effectiveness of treatment, the author commented that untreated control would be difficult to obtain in future study. In conclusion, it is generally agreed that the treatment of idiopathic precocious puberty with LHRHa improves the final adult height especially in the younger age group. Non responders may result from inadequate duration of treatment, delayed start of treatment or incomplete suppression of hypothalamic-pituitary--gonadal axis.

Treatment with LHRHa is safe. Side effects are uncommon with local tenderness and hypersensitivity reaction. Long term treatment may impair the bone mineral density but the effect is minimal. The decision to stop treatment require discussion with the patient and their family and would depend on the adult height prediction, acceptable age of puberty and patient's compliance. Reproductive axis suppression are completely reversible upon cessation of treatment. Long term side effect has not been reported.

References

1. Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in girls. Arch Dis Child 1969;44:291-301.

2. Marshall WA, Tanner JM. Variation in the pattern of pubertal changes in boys. Arch Dis Child 1970;45: 13-23.

3. Huen KF. Secular trend in the sexual maturation of Southern Chinese girls. Acta Paediatr (In press)

4. Wong GWK. Secular trend in the sexual maturation of Southern Chinese boys. Acta Paediatr 1996;85:620-1.

5. Brook CG. Precocious puberty. Clin Endocrinol 1995;42:647-50.

6. Culter GB. Effect of LHRH agonists on final height in LHRH dependent precocious puberty. Acta Paediatr 1993;388(Suppl):62-8.

7. Paul D. Long term effect of gonadotrophin releasing hormone agonist therapy on final and near final height in 26 children with true precocious puberty treated at a median age of less than 5 years. J Clin Endocrinol Metab 1995;80:546-51.