Precocious Puberty

The onset of puberty is an important milestone for individuals as well as socially and culturally. It is also an indicator of public health.¹

Precocious puberty is the appearance of signs of pubertal development at an abnormally early age. In girls this has traditionally been considered to be 8 years, although in recent years in the United States it has been recognised that normal puberty (particularly breast signs and pubic hair) can begin as young as 6 years. In boys onset of puberty before age 9 is considered to be precocious.²

Racial differences are significant.^{2 3} Over the last 50 years in the United States there has been a trend towards earlier puberty with particularly earlier onset of menarche in girls. Evidence in boys is less reliable but puberty in boys is probably starting earlier as well. However in the United Kingdom any decrease in the menarcheal age over the last 20 to 30 years has been small (probably less than 6 months) particularly when compared with the reduction of a year or more reported in many European countries between the late 19th and mid 20th centuries (better nutrition). ⁴ Any such earlier development now is not necessarily healthy and more studies into the possible environmental causes of this have been called for.^{3 1}

• The incidence and prevalence of precocious puberty depends on defining what is abnormal and accurate assessment of the onset of puberty. This has become something of a thorny issue recently.¹ In 1999 new guidelines from the USA recommended that puberty be considered precocious only with appearance of breast development or pubic hair before age 7 in white girls and before age 6 in black girls.²
• It is estimated that in the USA, using these definitions, 4-5% of girls from both racial groups exhibit precocious puberty
• Racial differences are significant. An analysis of the National Health and Nutrition Examination Survey (NHANES) from the USA showed that black girls enter puberty earliest, followed by Hispanic and then white girls. These differences were also shown to be independent of certain social and economic factors.¹
• Obesity also contributes to earlier puberty ⁵
• Figures for boys are harder to find. It is estimated that only between 10 and 20% of cases referred for precocious puberty are boys. Precocious puberty is rarely idiopathic in boys and early signs of puberty in boys is a particular cause for concern.⁶ It is important to point out that if precocious puberty is defined by variation from the mean (say more than 2 standard deviations), then the frequency of precocious puberty should be the same in both genders. In practice girls present more often as described because most girls have idiopathic central precocious puberty (see below).
• In Europe earlier puberty has also been reported, particularly in warmer climates ⁷
• Reports also suggest higher incidence of precocious puberty in girls adopted in Western Europe from underdeveloped countries.⁷

It is worthwhile describing normal puberty, particularly as abnormal forms of early puberty are both abnormal in character and abnormally early.

Normal Puberty - Endocrine control

The onset of puberty is signalled by the secretion of pulses of gonadotrophin releasing hormone (GnRH). Prior to puberty various mechanisms suppress onset of puberty (both via hormonal feedback and central neural suppression of GnRH release).
The hypothalamo-pituitary-gonadal axis starts working in the fetus and shortly after birth concentrations of sex hormones and gonadotrophins (leutinizing hormone, LH, and follicle stimulating hormone, FSH) are around the same levels as in adults. They reduce in the early months and pulsatile gonadotrophin releasing hormone (GnRH) reduces in childhood before increasing in frequency and amplitude before puberty.⁶ It progresses from occasional pulsatile GnRH secretion, to nocturnal secretion and on to 24 hour secretion. It has been postulated that the trigger for puberty comes from higher centres and is under partly neural control with genetics playing a part.⁸

Puberty in girls

• History: it is important when taking a history in adolescents to consider use of language and comprehension by the patient. They may not fully understand some terms but be reluctant to admit this. They may use language without fully understanding the words and terms used.
  • Breast enlargement, occasionally initially unilateral, is the first obvious sign of puberty and occurs on average between 10 and 11 years of age
    
  • Pubic and axillary hair growth in girls is a sign of adrenal androgen secretion. It starts at about the time of apocrine gland sweat production and the common complaint of axillary odour.
  • Menarche usually occurs about 2-3 years after the start of breast development (thelarche). The median age of menarche is around 13 years in contemporary British teenagers (12 years 11 months).⁴
  • The growth spurt occurs early in female puberty. It is usually maximal (about 8 cms/year) during tanner breast stages 2 and 3.⁶It reduces to 4cm/year at menarche.
• Examination: gynaecological examinations should be approached sensitively and only performed if absolutely necessary. Vaginal examination should only be performed if the patient is already sexually active. Rectal examination should never be performed in this context as information can be better gathered by, for example, use of ultrasound.
  • It is important to examine patients when they are in the supine position to help distinguish true breast enlargement from fat. Breast buds may initially be unilateral. Gradually the breast diameter increases and the areola darkens and becomes more prominent.
  • Genital examination may reveal pubic hair and changes in the vaginal mucosa (from red prepubertally to pastel pink, moist mucosa of the oestrogenised vagina). Clitoral enlargement and acne suggest androgen excess and virilisation.
  • Mild acne in early puberty is normal, but rapid onset and progression of acne again suggest androgen excess

Puberty in boys

• History:
  • The first signs of puberty often go unnoticed. Testicular enlargement can be detected quite early, but is often subtle enough in the early stages to go unnoticed. It usually occurs between age 12 and 13 years. The prepubertal testis is about 2 mls in diameter with puberty taken to begin when a volume of around 4mls is attained.
  • Penile and scrotal enlargement occur typically about a year after testicular enlargement is noticed
  • Pubic hair typically appears at a similar time
  • The growth spurt occurs later than in girls, possibly because testosterone is less of a stimulus to growth hormone responsiveness (than oestradiol in girls) and is required in relatively higher concentrations of testosterone are needed to produce the same anabolic effect.⁶A greater and later growth spurt occurs in boys and ultimately achieves an average 12.6 cm greater height in adult men. The growth spurt is on average 2 years later than girls and ceases only 1 year later.
• Examination:
  • Enlargement of testes depends on increased FSH. A Prader orchidometer (string of different volume 'beads'/testes for comparison by the examiner) is taken to herald onset of nocturnal pulsatile gonadotrophin at a volume of 4mls. Progressive signs of androgen excess without commensurate increase in testicular volume should raise concern about precocious pseudopuberty (androgenic effect from another source such as congenital adrenal hyperplasia, or CAH, testicular tumours etc).
  • Signs of change in penis (growth), scrotum (reddening and thinning) and pubic hair growth follow 1-2 years after testicular enlargement
  • Pubic hair growth without other changes (premature adrenarche) suggests adrenal androgen production (CAH, Cushing's, adrenal tumour)
  • Later signs include growth spurt, voice deepening, acne and facial hair.

It is interesting to note that although girls are generally considered to mature earlier than boys, the differences in timing are less than generally perceived.⁶ Testes require higher levels of gonadotrophin stimulation than ovaries, hence the later puberty, but on average spermache occurs at about the same time as menarche with attainment of reproductive capability being achieved at about the same age.

Premature pubarche

This refers to early appearance of pubic hair (with or without axillary hair) but without other signs of puberty. Apocrine glands causing adult body odour accompany these changes. These are signs of androgen activity. This may be:

• Weak androgens from adrenal glands (premature adrenarche). Temporarily the pubic hair development is in advance of breast development and other changes. Generally this is not a cause for concern.
• Signs of severe androgen excess (clitoral enlargement, growth spurt etc) suggests severe androgen excess and needs further investigation. This can be caused by:
  • Congenital adrenal hyperplasia
  • Virilising tumours, for example in the adrenal glands, the ovary or a dysgenetic testes
  • Cushing syndrome.
• Exogenous androgens could also cause these changes (eg contact with topical androgen preparations).

In a pubertal girl androgen activity may evidence of polycystic ovarian syndrome.

Premature thelarche

This refers to early appearance of breast development without other signs of precocious puberty (such as growth spurt, uterine changes, vaginal changes etc). Typically this is seen under age 3 years and in early months is caused by maternal oestrogens. It is a benign condition confirmed by:

• Normal growth with appropriate bone age. (ie no growth spurt)
• Minimal increase in breast tissue with time (can even decrease)
• Appropriate uterine dimensions for age (Ultrasound) with normal endometrial echo and no vaginal bleeding
• Absence of other signs of puberty (eg no thickening or pigmentation of areola, no pubic hair etc).

The aetiology is unknown although small transient ovarian cysts or exogenous oestrogens (phytooestrogens in food for example) may be implicated. The natural history is of fairly static breast development before true puberty eventually ensues at the normal time. It needs no investigation beyond clinical examination, growth assessment and pelvic ultrasonography.

Gonadotrophin-dependent precocious puberty (or central precocious puberty,CPP)

This involves premature activation of the hypothalamic-pituitary-gonadal axis (HPG). Most patients (especially girls) suspected of having CPP are normal (but lie at one end of the normal distribution curve). However MRI is often necessary to confirm this and exclude CNS abnormalities associated with CPP.⁹ In boys MRI is nearly always required.⁶ American guidelines for scanning may not be safe in European countries.¹⁰Such CNS abnormalities include:

• Tumours, including gliomas, astrocytomas and human chorionic gonadotrophin (HCG) secreting germ cell tumours
• CNS trauma or injury (causes include abscess, radiation, surgery etc)
• Hamartomas of the hypothalamus
• Congenital disorders such as hydrocephalus and arachnoid cysts.

Where no such CNS abnormalities are found the causes of an early, normal puberty are:

• Genetic. Often early puberty is familial and autosomal dominant in inheritance
• Obesity. In girls early puberty is associated with increased body mass index (BMI). This is particularly the case in white girls. Obesity is not associated with early puberty in boys.

Gonadotrophin-independent precocious puberty (or precocious pseudopuberty)

In such cases the presence of sex hormones is independent of the HPG. The gonad matures independently of GnRH stimulation. Typically:

• Levels of testosterone and oestradiol are at pubertal levels (in the absence of gonadotrophin pulsatility)
• LH and FSH are at prepubertal levels
• Flat GnRH response
• No response to treatment with GnRH analogues.

The causes are much less common (about 20% of cases of precocious puberty) and some of the specific types are rare. The list of causes is long and includes:

• CAH. There are a variety of types. These are autosomal recessive disorders of adrenal steroidogenesis leading to excess adrenocorticotrophic hormone (ACTH), hence excess cortisol precursors which get pushed into the androgen pathway leading to androgen excess.
• HCG secreting tumours. These can be found in:
  • Liver (hepatomas, hepatoblastomas)
  • Choriocarcinomas (of gonads, pineal gland, mediastinum etc).
• Adrenal tumours (rare)
• Ovarian tumours. These can cause either masculinisation or feminisation.
• McCune-Albright syndrome (MAS). Cases are sporadic, 95% female and can present at any age. Average age of puberty is 3 years. There is a molecular basis to the disorder involving the cAMP signaling pathway. Affected individuals are at risk of multiple endocrinopathies including thyrotoxicosis, Cushing syndrome, acromegaly, hyperparathyroidism etc.
• Testotoxicosis (or familial male precocious puberty) This is an autosomal dominant condition with 90% penetrance. The defect is in the LH receptor which activates in the absence of LH and HCG. It is characterised by progressive pubertal changes, rapid physical growth, skeletal maturation and sexually aggressive behaviour in the first 2-3 years of life.
• Hypothyroidism or van Wyk-Grumbach syndrome. The mechanism is unknown (possibly to do with LH like effect of TSH). Growth unusually is arrested rather than accelerated.

There is a long and varied list of available investigations. However, these are used selectively in the diagnostic process (see management below) and after full clinical assessment. It is important to establish whether the physical findings (secondary sexual characteristics, growth, bone maturity etc) are consonant or not. Tests available to further refine the diagnosis are:

• Levels of sex steroid. Some useful points:
  • Early morning testosterone in boys is higher in early puberty
  • Levels of testosterone over 30ng/dL are consistent with early puberty but it is laboratory dependent
  • Oestradiol levels are a less reliable measure of stage of puberty in girls
  • Pubertal levels of sex steroid are found in gonadotrophin-independent precocious puberty.
• Gonadotrophins(LH and FSH).
  • A random LH is now the best test for CPP
  • Random FSH will not distinguish prepuberty from puberty
  • Low or prepubertal levels with high sex steroid levels are found in gonadotrophin-independent precocious puberty.
• Thyroid function tests. These are not routinely required, but measured when hypothyroidism is suspected (slowing of growth with galactorrhoea and signs of hypothyroidism).
• Adrenal steroid precursors. These are measured if CAH suspected.
• HCG can be measured when HCG-secreting tumours are suspected.
• Urinary 17-ketosteroids.These can be measured to quantify the amount of adrenal androgens being produced.
• Diagnostic imaging. What is required depends on the diagnostic path being followed.
  • Ultrasound.
    • Pelvic ultrasound. This is essential in gonadotrophin independent precocious puberty (precocious pseudopuberty) to detect ovarian tumours or cysts. Although not required in CPP it will demonstrate changes in ovaries and uterus.
    • Other ultrasound.Testicular and adrenal ultrasound can help establish diagnosis of tumours, but better imaging is ultimately achieved with MRI with adrenal tumours.
  • Plain radiographs. Hand and wrist X-rays for bone age. If bone age within 1 year of chronological age either puberty has not started or has only just started. If bone age 2 years advanced then puberty has started.
  • Bone scan. This is not often required but useful with MAS.
  • Brain MRI. This should be performed in all males with sexual precocity and in patients with neurological signs or symptoms. It is used selectively in girls.⁹
  • Pelvic MRI. In girls this can be useful to assess uterine function and ovarian pathology.
• Other tests.
  • GnRH stimulation test. The LH and FSH levels are measured sequentially after dose of GnRH. There is a flat response in gonadotrophin-independent precocious puberty. It is less useful in CPP.¹¹
  • Leuprolide acetate stimulation test. Developed as an alternative as GnRH difficult to obtain.

• A good understanding of normal and abnormal puberty is essential
• Assessment begins with history and examination to determine which of the main diagnostic criteria are likely to fit
• Assessment of stage of puberty, growth and bone age is essential
• Selective use of investigations will help confirm the diagnosis
• Early referral for expert assessment and diagnosis is essential
• Early puberty can adversely affect growth and delay can compromise final height
• Treatment will depend on the diagnosis and the cause of the precocious puberty.

Often with CPP in the absence of brain pathology, if the child is well adjusted, treatment for pubertal changes alone may not be required. This is particularly true if the puberty progresses slowly and there is unlikely to be serious compromise of adult height. However puberty can be arrested and growth hormone given if the height prognosis is poor. Examples of treatment include:

• Surgery. Tumours may require resection. Unfortunately resection rarely causes regression of the pubertal changes.
• Medical treatments, for example:
  • Gonadotrophin-releasing hormone agonists (GnRH agonists)These have been in use since the 1970's and work by decreasing LH and FSH levels. They are used in CPP as well as in a range of other aetiologies including MAS and testotoxicosis.
  • Glucocorticoids.These are used for CAH.
  • Testolactone is an aromatase inhibitor (therefore inhibits steorid biosynthesis) used most commonly for MAS but also in testotoxicosis
  • Tamoxifen may be used in MAS
  • Ketoconazole may be used (for example in testotoxicosis) to inhibit steroid biosynthesis
  • Cyproterone acetate may be used for anti-androgen action
  • Flutamide is used again to counter androgen excess
  • Medroxyprogesterone, a progesterone analogue, has also been used.⁶

The key to an excellent prognosis is, in general terms, early recognition and treatment.

CPP

Without treatment most girls aged 6-8 years at the onset of their puberty will achieve adult height within the normal range. Treatment significantly improves final height and should be considered when:

• Predicted height is less than 4'11'' or below target height (average of parents' heights less 2.5'')
• Bone age is advanced
• And/or patient 's height is below 25th centile.

Gonadotrophin-independent precocious puberty

This depends on the aetiology. The possible diagnoses already discussed cover a range of possible outcomes. With early recognition and treatment the prognosis can be excellent.

The most common pitfalls are failure to recognise precocious puberty followed by failure to refer. The significance of virilisation is often overlooked, or diagnosed late. Brain tumours, particularly in boys, causing precocious puberty are overlooked:

• Ensure that boys with early puberty particularly are referred and fully investigated with head MRI
• Ensure generally that patients with precocious puberty are recognised early and referred
• Knowledge of normal puberty assists recognition of the abnormal
• Explanation and reassurance can be given more easily with better knowledge of likely diagnosis, investigation and treatment.