Paediatric medicine - Investigating delayed puberty

Often simple reassurance is all that is needed but be aware of signs to investigate.

Polycystic ovary syndrome: consider in girls of normal height with secondary amenorrhoea
Polycystic ovary syndrome: consider in girls of normal height with secondary amenorrhoea

The timing of the start and subsequent milestones of normal puberty has a wide range, therefore it is important to appreciate the considerable variability in healthy adolescents.

Puberty starts with breast development in girls around age 11 years and is associated with rapid growth.

No signs of this happening in a girl over 13 years warrants further investigation. The lack of breasts and no growth spurt is usually obvious to girls and their families.

Primary failure of menstruation by 15 years needs evaluating, but if the rest of puberty is slow then this is probably part of late normal development.

Boys' first signs of puberty are much more subtle - just early testicular enlargement - normally around age 12 years. Little else occurs in the early stages and so these early signs are often not recognised by boys who think nothing is happening to their pubertal development.

The peak growth spurt and other changes such as voice breaking, muscle bulking and facial hair growth are not usually present for another two years. Most worried boys have late normal puberty and clinical examination demonstrating growth of the testes is all that is needed for reassurance.

No evidence of testis growth or other signs beyond 14 years constitutes delayed puberty. A reason should always be found.

Expected delayed puberty
Long-standing chronic childhood conditions may delay growth and puberty, especially where inflammatory processes are present and corticosteroids have been used in the treatment regimen.

Despite an obvious cause, pubertal assessment is necessary as active treatment of the delay in growth and puberty can improve the growth prognosis, reduce long-term risk of osteoporosis and boost self-esteem, so a referral is beneficial.

Simple or constitutional delay of puberty is often accompanied by growth delay and can be familial. A detailed family history can be helpful, but this diagnosis should be made only when all other reasons for late puberty have been excluded.

Unexpected delay
An evaluation of the relationship between the rate of growth and progress through puberty or lack of it is a helpful start.

Normal height (no short stature), but with true pubertal delay or primary amenorrhoea: Conider central causes of absent or reduced gonadotropin secretion. This may also occur in eating disorders.

Rarer causes include Kallmann syndrome - anosmia, colour blindness and midline defects; sex chromosome variations (e.g. XXY Klinefelter's syndrome or XXX syndrome) may slow the pubertal process.

Normal height with secondary amenorrhoea: Consider polycystic ovarian syndrome (PCOS), especially if overweight or signs of hyperandrogenism are present.

Normal or short stature, halted growth and delayed puberty (primary amenorrhoea) or pubertal arrest: High suspicion here of severe organic disease such as a brain tumour or Crohn's disease. This is a red flag that requires urgent referral.

Chromosomal variations such as Turner syndrome (45,X and mosaics) should also be excluded.

Short stature with appropriately slow growth and pubertal delay: Usually constitutional delay, but hidden organic pathology (e.g. coeliac disease) should always be ruled out.

Primary care investigations

Routine first-line:
FBC and CRP or ESR to exclude anaemia, iron deficiency, malnutrition and hidden inflammatory disease.

U&Es and LFT to exclude renal and liver diseases.

Bone profile - an inappropriately low for age alkaline phosphatase confirms slow growth.

Coeliac antibodies (tTG) to exclude cryptic coeliac disease.

TSH and free T4 to exclude hypothyroidism (central hypothyroidism cannot be excluded on TSH alone)

Second-line (endocrine):
FSH and LH - low levels are associated with central or constitutional delay. Elevated levels are associated with primary testicular or ovarian disorder.

Prolactin - significant elevation is suggestive of pituitary microadenoma.

Early morning estradiol (girls) - low but detectable levels suggest pubertal development is imminent.

Early morning testosterone (boys) - low but detectable levels suggest pubertal development is imminent.

Elevated testosterone (female range) and LH:FSH ratio is suggestive of PCOS in girls.

The next steps
The presence of early pubertal signs associated with an appropriately slow (boys) or fast (girls) growth rate is probably normal, so a repeat assessment of growth and puberty in primary care three to six months later is usually all that is required for reassurance purposes.

A mismatch between growth and puberty, or genuine delay of puberty should merit a referral. First- and second-line investigations conducted in primary care may be very helpful.

Secondary amenorrhoea with a suspicion of PCOS can be investigated further with fasting glucose, insulin and lipids. Pelvic ultrasound scans are very operator dependent in this age group.

Treatment options
Exclusion of a serious organic disease or a chromosome variation is the primary goal in an adolescent presenting with true delayed sexual development.

If all is normal, and puberty is just late, simple reassurance is all that is needed.

Delay, especially when accompanied by short stature, can produce anxiety, depression and low self-esteem, isolation and school refusal.

As this is almost always a problem for boys due to the difference in physiological timing of events, a short-term course of around three to 12 months' treatment with low-dosage testosterone can boost growth, pubertal progress and morale.

Treatment options include monthly depot testosterone esters or daily oral capsules. Transdermal testosterone is under evaluation in this age group.

Testosterone is usually continued until there is clear evidence of spontaneous puberty (testicular growth).

The duration and dosage of therapy should be monitored by a paediatric endocrinologist as overdosage or excessively long courses can reduce the period of pubertal growth.

Growth hormone is not necessary unless there is a proven deficiency.

Therapeutic management of simple delayed puberty is rarely required in girls, but very low doses of ethinyl estradiol are the mainstay of treatment.

  • Professor Butler is consultant in paediatric and adolescent medicine and endocrinology, University College London Hospital and honorary professor UCL Institute of Child Health, Great Ormond Street Hospital for Children.

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