Puberty - Normal and Abnormal

• Puberty is the growth process associated with appearance of both primary and secondary sexual characteristics in children.¹
• It occurs between 8 and 14 years of age in girls and 9 and 14 years of age in boys.
• The changes encompass aspects of sexuality together with cognitive development and changes in relationships with family and peers.
• It is important for doctors treating children to have an understanding of normal puberty so that children with abnormal puberty can be recognised and appropriately investigated.
• It is important to understand the range of normal and differences between populations.^2,3

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 (leutinising hormone, LH, and follicle stimulating hormone, FSH) are around the same levels as in adults.
• However these levels reduce in the early months after birth and pulsatile gonadotrophin releasing hormone (GnRH) reduces in childhood before increasing in frequency and amplitude before puberty.⁴
• The occasional pulsatile GnRH secretion progresses 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.⁵
• For 2 years before puberty there is a rise in levels of adrenal androgens that can sometimes result in the early appearance of pubic hair and spots. This is also initiated by the nocturnal secretion of pulses of GnRH from the hypothalamus.

Normal 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).⁶
  • The growth spurt occurs early in female puberty. It is usually maximal (about 8 cms/year) during Tanner breast stages 2 and 3.⁴ It reduces to 4cm/year at menarche.
• Examination:
  • Puberty leads to the enlargement of the sex organs and external genitalia as well as thickening of the endometrium and vaginal mucosa.
  • 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.

Tanner stages of puberty in girls are summarised in the table below.⁷

Normal 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.⁴ A 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:
  • Testicular growth starts as early as ten years of age, associated with enlargement of seminiferous tubules, epididymis, seminal vesicles and prostate.
  • 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).
  • Approximately half of boys have some degree of breast hypertrophy.
  • Later signs include growth spurt, voice deepening, acne and facial hair.The growth peak starts 2–3 years earlier in girls. Growth spurts start with the hands and feet and moves proximally to finish with the trunk.

Stages of normal puberty (Tanner stages) in boys are shown in the table below.⁷

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.⁴ Testes require higher levels of gonadotrophin stimulation than ovaries, hence the later puberty. However, on average spermache occurs at about the same time as menarche with attainment of reproductive capability being achieved at about the same age.

There are many causes of abnormal puberty.¹ The main aim of assessment is to determine those children with an underlying pathological abnormality from those with constitutional and benign pubertal changes. It is important to recognise abnormal timing and progression of puberty. This may require a combination of clinical assessment, investigations and expert advice.

History

• Take a full history of previous growth and development.
• Record the timing and sequence of physical milestones and behaviour changes of puberty.
• Record full medical and surgical history.
• If individual is underweight and has delayed puberty take a nutritional history.
• Detail any family history of early or delayed puberty and any genetic disease.

Physical examination

• Plot growth velocity on growth chart. Has there been a change compared to old records?
• Most important systems to examine are neurological and endocrine.
• Look for evidence of thyroid or other endocrine dysfunction.
• Optic fundi, visual fields and sense of smell should be checked to look for evidence of a pituitary tumour.
• The genitalia and body habitus should be examined and the stage of puberty documented.
• Photographs are useful to document the stage of puberty. However such clinical photographs need appropriate consent and are best undertaken in hospital medical photography departments.

There is a long and varied list of available investigations. However, these are used selectively in the diagnostic process 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 include:

• Assessment of bone age An x-ray of the left wrist can be used to determine skeletal age compared to chronological age.
• Further investigations may be needed to categorise/diagnose early or delayed puberty. Usually such detailed investigations will be conducted in secondary care under expert guidance. These may include:
  • Blood tests:
    • FSH/LH levels, oestrogen assay
    • 17-OH progesterone/DHEA assay
    • Testosterone levels
    • Prolactin levels
    • Beta-HCG
    • TFTs
    • Gn-RH assay
  • Diagnostic imaging may be required (depending on the likely diagnosis):
    • Pelvic ultrasound:
      • Essential in gonadotrophin independent precocious puberty (precocious pseudopuberty) to detect ovarian tumours or cysts
    • Other ultrasound:
      • Testicular (tumour detection)
      • Adrenal ultrasound (tumour detected but better imaging with MRI)
    • Plain 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- puberty has started
    • Brain MRI,⁸ for example in:
      • All males with sexual precocity
      • Patients with neurological signs or symptoms
    • Pelvic MRI:
      • In girls (to assess uterine function and ovarian pathology)
  • Chromosomal analysis (to detect chromosomal abnormality)

Delayed puberty

• May be suggested by short stature or in boys with:⁴
  • No testicular enlargement by age 14 years. Can assess with Prader orchidometer beads
  • Pubic hair absent by age 15
  • >5 year between the start and completion of growth of the genitalia
• May be suggested in girls with:
  • Absence of breast development by age 14 years
  • Pubic hair absent by age 14
  • >5 years between the start and completion of breast growth
  • Menarche has not occurred by age 16
• Causes of delayed puberty:
  Constitutional delay is the commonest cause in boys (>50%). The commonest cause in girls is Turner's syndrome (>80% girls have pathological cause of delayed puberty).⁹
  • Hypogonadotrophic:
    • Constitutional (sporadic or familial)
    • Chronic illness (renal failure, Crohn's disease, thalassaemia)
    • Malnutrition (anorexia, cystic fibrosis, coeliac disease)
    • Exercise (gymnasts)
    • Polycystic ovarian disease
    • Tumours or destructive lesions of hypothalamus/pituitary (craniopharyngioma, meningioma, vascular lesions)
    • Hypothalamic syndromes (Laurence-Moon-Biedl, Prader-Willi, and Lyndi's syndromes)
    • Hypothyroidism (more often associated with precocious puberty, here it is associated with autoimmune oophoritis)
    • Suppression secondary to:
      • Hyperthyroidism
      • Hyperprolactinaemia
      • Cushing's syndrome
      • Congenital adrenal hyperplasia
  • Hypergonadotrophic:
    • Congenital:
      • Turner's
      • Kleinfelter's syndromes
    • Acquired:
      • Irradiation
      • Surgery
      • Chemotherapy
      • Testicular torsion, trauma or castration
      • Infection (mumps rarely causes pre-pubertal damage)
      • Autoimmunity

Precocious puberty

See precocious puberty.
Usually defined as the onset of secondary sexual characteristics before the age of 8 years in girls (though some sources lower this to 7 years) and 9 years in boys. 5 times more common in girls. Precocious puberty is usually a benign central process in girls but in boys a pathologic peripheral cause should be excluded (found in ~50%).

• Premature thelarche and premature pubarche:
  • Thelarche is the beginning of breast development and pubarche the first appearance of pubic hair.
  • Early appearance of these characteristics is more common than true precocious puberty.
  • Benign variants may manifest as breast development in girls <3yrs which spontaneously regresses, and pubic hair in both boys and girls <7yrs due to adrenal androgen secretion in middle childhood (some sources consider this may be a precursor of polycystic ovary syndrome and recommend follow-up).
  • Examination will be normal or there may be a or slight advance in growth curve.
• Gonadotrophin-dependent precocious puberty:
  • Idiopathic (sporadic or familial)
  • Congenital (hydrocephalus)
  • Acquired (irradiation, surgery, and infection)
  • Tumours (hamartomas, gliomas, and pineal tumours)
  • Hypothyroidism
  • Russell-Silver syndrome
  • McCune-Albright syndrome
• Gonadotrophin-independent precocious pseudopuberty:
  • Normal pattern of puberty absent
  • May include for example:
    • Virilisation of girl (congenital adrenal hyperplasia)
    • Feminisation of boy (oestrogen producing leydig cell tumour)