Delayed puberty

SYMPOSIUM: ENDOCRINOLOGY

Delayed pubertyGary Butler

Normal UK pubertal milestones

Girls

Age (years) Mean 2nde98th centile range

Breast development

(Tanner stage 2)

11.0 8.2e13.8

Menarche 13.0 11.0e15.0

AbstractThe onset of puberty may be late e in the latter part of the predicted

normal range or truly delayed e beyond this range. This is usually

regarded as 13 years in girls and 14 years in boys. A height plot beyond

the prepuberty phase limit on the UK-WHO 0e18 year charts also defines

delayed puberty. The initial approach requires a detailed history and clin-

ical examination to exclude other medical or psychological problems. The

presence or absence or pubertal signs should be documented. Investiga-

tions should be targeted at ruling out any medical causes and deter-

mining whether the delay is due to central gonadotrophin deficiency or

a gonadal disorder. Physiological or constitutional delay is more common

in boys but is a diagnosis of exclusion. Treatment may be given using low

doses of sex steroids, testosterone or oestradiol initially in a short course

of 3e6 months, but continuing in escalating doses mimicking the normal

course of puberty, watching regularly for the spontaneous resumption of

progress and gonadotrophin secretion. Counselling, reassurance and

support are key elements in the management of adolescents with delayed

puberty.

Keywords breast development; gonadotrophin; growth chart; Kallmann

syndrome; menarche; oestradiol; puberty phase; Tanner stage; testicular

enlargement; testosterone

What constitutes late or delayed puberty?

There is a wide range in the timing, start and subsequent mile-

stones of normal puberty so it is important to appreciate the

considerable variability in healthy adolescents (Table 1). Puberty

starts with breast development in girls around age 11 years and is

associated with rapid growth, so no signs of this happening in

a girl over 13 years warrants further investigation. The lack of the

appearance of breasts and an absent growth spurt is usually

pretty obvious to girls and their families. Primary failure of

menstruation by 15 years needs evaluating, but if the rest of

puberty has been slow then late onset of menstruation is prob-

ably just part of slow normal development.

Boys’ first signs of puberty are much more subtle e just early

testicular enlargemente normally around age 12 years. Very little

else occurs in the early stages and so these early signs are often not

recognized by boys who think nothing is happening to their

pubertal development. The peak of the growth spurt and other

changes such as voice breaking, muscle bulking and facial hair

growth usually do not appear for another 2e3 years. Most worried

boys just have late-normal puberty and clinical examination

Gary Butler MD FRCP FRCPCH is Consultant in Paediatric and Adolescent

Medicine and Endocrinology, at University College Hospital, London

and Great Ormond Street Hospital for Children, London and Honorary

Professor at UCL Institute of Child Health, London, UK. Conflicts of

interest: none.

PAEDIATRICS AND CHILD HEALTH 21:7 306

demonstrating growth of the testes is all that is needed for reas-

surance. No evidence of testis growth or other signs over 14 years

constitutes delayed puberty. A reason should always be found.

A more unusual problem is a normal commencement of

puberty but a subsequent halting with failure to progress or

complete sexual development. This is always worrying and

needs a thorough investigation along a similar thought process to

that which delays the onset. The most common presenting

complaint is secondary amenorrhoea. The details of assessment

are outside the scope of this review.

The new UK-WHO 0e18 year growth charts contain two

puberty zones. The starting zone clearly defines the acceptable

range for the onset of puberty in each sex. Failure to begin with

any sign of development at an age beyond this zone defines

puberty as delayed. The second or finishing zone delineates the

normal age range for the completion of sexual development.

Using a similar approach, the lack of completion of puberty e

menstruation is the defining feature in girls, and failure to

develop breaking of the voice and facial hair in boys are the

obvious signs that puberty has not progressed.

When might delayed puberty be expected?

Longstanding 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 the long-term risk of osteoporosis

and can boost self-esteem, so careful evaluation may be benefi-

cial. Delayed puberty may be due to an unrecognized chronic

condition so the initial approach to investigation always starts

from a general footing.

Monitoring pubertal progress is mandatory in all adolescents

with chronic conditions as failure to progress through puberty

may also be a sign of disease reactivation, poor adherance to

medical treatment or the development of complications of the

condition or its treatment. Common chemotherapy and radio-

therapy regimens used in childhood cancer treatment are

a classic example of this.

Boys

Age (years) Mean 2nde98th centile range

Testicular enlargement

(Tanner stage 2)

12.0 9.8e14.2

Peak of growth spurt 14.0 11.8e16.2

Table 1

� 2011 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.paed.2011.03.009


Simple or constitutional delay of puberty is often accompa-

nied by growth delay and can be familial. So a detailed family

history can be helpful, but this diagnosis should be made only

when all other reasons for late puberty have been excluded.

The history

When taking the history, the first focus should be on general

health and any previous medical problems or treatments.

Knowing about exercise taken (too much or too little) is helpful.

Specific enquiry into eating habits and bowel frequency may point

to psychological conditions such as eating disorders, commonly

anorexia nervosa or a suspicion of inflammatory bowel disease.

Do not forget the family history as a tendency to late puberty

may be a family characteristic. As specific enquiry into anosmia,

colour blindness or other midline defects such as cleft palate and

undescended testes may lead to identification of specific gene

defects associated with gonadotropin deficiency ie Kallmann’s

syndrome (Table 2).

What should be done when delayed puberty is unexpected?

An evaluation of the relationship between height, the rate of

growth and progress through puberty or lack of it is a helpful

starting point.

Normal height (ie no short stature), but with true pubertal delay

or primary amenorrhoea:

Consider central causes of absent or reduced gonadotropin

secretion. This may also occur in eating disorders.

Rarer causes: Kallmann syndrome e anosmia, colour blindness

and midline defects; sex chromosome variations (eg XXY Kline-

felter syndrome or XXX) may slow the pubertal process.

Normal height with secondary amenorrhoea:

Consider polycystic ovarian syndrome, especially if overweight

or signs of hyperandrogenism are present.

Causes of delayed puberty

Central

C Hypopituitarism, primary and secondary

C Tumours and their treatments

C Primary gonadotrophin deficiency (Kallman’s syndrome)

C Psychological (anorexia)

GonadalC Agenesis/dysgenesis

C (Sex) chromosome abnormalities

C Irradiation/chemotherapy

C Complete androgen insensitivity syndrome (presents as

delayed menarche)

General or systemic

C Chronic illness (often cryptic-requires investigation)

C Hypothyroidism

C Most common but diagnosis of exclusion: maturational

(or constitutional) delay

Table 2


Normal or short stature, but with 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: Red flag e urgent investigation

needed.

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 (eg

coeliac disease, inflammatory bowel disease, midline brain

tumours) should always be ruled out.

What investigations are helpful in a stepwise approach to

diagnosis?

Routine first-line (general)

Full blood count and an inflammatory marker (CRP or ESR) e to

exclude anaemia, iron deficiency, malnutrition and hidden

inflammatory disease eg Crohn’s disease.

U & E, LFT e to exclude renal and liver diseases.

Bone profile e an inappropriately low for age alkaline phos-

phatase confirms slow growth.

Coeliac antibodies (tTG) e to exclude cryptic coeliac disease.

TSH and free T4 e to exclude hypothyroidism (central hypo-

thyroidism cannot be excluded on TSH alone).

Second-line (endocrine)

FSH, LH e low levels associated with central or constitutional

delay. Elevated levels associated with a primary testicular or

ovarian disorder.

Prolactin e significant elevation suggestive of pituitary macro or

microadenoma.

Early morning oestradiol (girls) e low but detectable levels

suggest pubertal development is imminent.

Early morning testosterone (boys) e low but detectable levels

suggest pubertal development is imminent.

Elevated testosterone (female range) and high LH:FSH ratio is

suggestive of PCOS in girls.

The next steps

The presence of early pubertal signs associated with an appropri-

ately slow growth rate in boys or fast growth rate in girls suggests

that the adolescent is probably a late-normal developer, so a repeat

assessment of growth and puberty 3e6 months later is usually all

that is required for diagnostic and reassurance purposes.

Low gonadotrophins and sex hormones or mismatch between

the normal association between growth and puberty points to

a central cause so in this case the patient must have an MRI scan.

Secondary amenorrhoea with a suspicion of PCOS can be

investigated further with fasting glucose, insulin, lipids and

testosterone or free androgen index (dependent on local labora-

tory practice). Pelvic ultrasound scans are very operator depen-

dent in this age group and thus not usually required.

Treatment options

Exclusion of a serious organic disease or a chromosome variation

is the primary goal in an adolescent presenting with true delayed



Approach to the treatment of prolonged physiologicaldelayed puberty in girls

C Start low-dose ethinyloestradiol as per induction of puberty

C Perform 6 monthly ovarian US to look for follicular activity and

thus evidence of gonadotrophin secretion

C Continuation of treatment is usually only required if there is

a defect in gonadotrophin regulation

Table 4

Approach to the treatment of prolonged physiologicaldelayed puberty in boys

C Continue dosage increments as per induction of puberty

C Use approx 6 monthly dose increases until there is evidence of

testicular growth which represents spontaneous gonadotrophin

secretion

C Total treatment may include several courses of testosterone

C Growth hormone is not necessary unless there is a proven

deficiency

Table 3


sexual development. If all is normal, andpuberty is just late, simple

reassurance & support and an understanding of the problem from

patient’s perspective is all that is needed. Delay, especially when

accompanied by short stature can produce anxiety, depression and

low self-esteem, isolation and school refusal. Counselling in life

style skills may be helpful. Repeating the clinical assessment for

progress in puberty may be welcomed for reassurance.

As delayed puberty is almost always an issue for boys due to

the difference in physiological timing of the physical events

between the sexes, a short-term course of low-dose testosterone

treatment for around 3e6 months can boost growth, pubertal

progress and morale. Treatment options include depot testos-

terone esters (Sustanon, Virormone) 50e100 mg given intra-

muscularly on a monthly basis, or oral testosterone undecanoate

capsules (Restandol Testocaps) 40 mg daily. Both are equally

effective. Transdermal testosterone (Testogel, Testim, Tostran) is

under evaluation in this age group but 10e20 mg daily is an

appropriate starting dose.

Testosterone is usually continued until there is clear evidence

of spontaneous puberty (testicular growth). Appropriate active

management of puberty does not adversely affect the long-term

growth prognosis (Table 3). The duration and dosing of therapy

should be monitored by a paediatric endocrinologist however as

overdosage or excessively long courses may reduce the period of

pubertal growth. The best approach requires an active manage-

ment of the growth and lack of secondary sex characteristics

whilst keeping a watchful eye on the resumption of normal

gonadotrophin secretion.


Therapeutic management of physiological delayed puberty is

rarely required in girls, but in such cases very low doses of

ethinyloestradiol starting with 1e2 mg daily are the mainstay of

treatment (Table 4).

Conclusion: cardinal points in the management of delayed

puberty

� Use all previous growth measurements and family information

� Think about the process of puberty as a whole

� Carefully plan your investigations

� Keep an open mind as to causes and consequences of the delay

� Manage the patient as an individual with appropriate

psychological support

� Keep a watchful eye on the resumption of gonadotrophin

secretion from a clinical perspective if using sex hormone

treatment. A

FURTHER READING

Banerjee I, Clayton PE. Puberty. Oxford textbook of medicine. 5th Edn.

OUP, 2010. 13.9.1, 1958e62.

Brook CGD, Clayton PE, Brown RS, eds. Clinical pediatric endocrinology.

Oxford: Blackwell, 2010.

Butler GE. Normal growth and its disorders. Oxford textbook of medicine.

5th Edn. OUP, 2010. 13.9.1, 1948e58.

Butler GE, Kirk JMW. Oxford specialist handbook of paediatric endocri-

nology and diabetes. OUP, 2011.

Kelnar CJH, Butler GE. Endocrine gland disorders and disorders of growth

and development. In: McIntosh N, Helms P, Smyth R, Logan S, eds.

Forfar and Arneil textbook of paediatrics. Elsevier, 2008: 409e512.



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Delayed puberty