Delayed puberty and pubertal failure

Malcolm Donaldson
Senior Lecturer in Child Health, Royal Hospital for Sick Children, Glasgow

Endocrine Nurses Training Course 2005, John MacIntyre Centre, The University of Edinburgh, 18 Holyrood Park Road, Edinburgh EH16 5AY, UK
30 August - 1 September 2005

Delayed puberty is arbitrarily defined as absence of signs of secondary sexual development in a girl aged 13 years or a boy aged 14 years.
In practical terms delayed puberty is delay in the onset, progression or completion of puberty sufficient to cause concern to the adolescent, parents or physician.

The following terms are helpful to consider:

• Pubertal failure: puberty that either fails to begin, or having begun, fails to complete
  (in which case the term mid-pubertal arrest is often used).
• Delayed menarche: first period after 15 years.
• Primary amenorrhoea: failure to start periods.
• Secondary amenorrhoea: cessation of established menses
• Oligomenorrhoea: infrequent periods (<6/year).

Classification of delayed and/or abnormal puberty

1. Central cause (hypothalamus and pituitary)
1. Central delay with an intact H-P axis
2. Central delay with an impaired H-P axis
2. Peripheral cause (gonads – ovaries and testes)

The table gives a working classification of delayed puberty and its causes.

Clinical assessment
A good working diagnosis can almost always be made by

• taking a thorough history
• making a proper assessment of growth, pubertal status and skeletal maturity
  (bone age)
• carrying out a sound physical examination

Most boys and girls with delayed puberty have simple constitutional delay in growth and adolescence (CDGA), and do not need detailed investigation.

History
Growth pattern. Adolescents with CDGA have a long-standing history of short stature with a widening gap between them and their peer group from secondary school entry onwards

General health. Ask about energy levels and any symptoms of chronic ill health. Asthma may be associated with delayed puberty, especially when inhaled steroids have been used.

Features/associations with gonadal impairment. Ask about a previous history of cryptorchidism, orchidopexy, and gonadal irradiation. Ask about sense of smell (for Kallmann’s syndrome).

Family patterns: Age at menarche in the mother and sisters, delayed growth spurt/voice breaking in the father and brothers.

Social and educational aspects. Occupation and lifestyle of the family (looking for any social problems). Learning disability in the patient may be a feature of a syndrome associated with delayed puberty (e.g. Noonan’s).

Examination

• Height, weight.
• Measured or (much less reliable!) reported parental heights.
• Measured or reported sibling heights.
• Pubertal staging – this must be done properly. An ultra-brief ‘peek’ to spare the patient’s feelings is a disservice to the patient! Same sex staging wherever possible.
• Nutrition.
• Dysmorphic features.
• General examination including fundoscopy, blood pressure measurement and search for clubbing.

Investigations
None if possible apart from bone age!
In selected cases:

Investigations for chronic disease

• Hb, ferritin, U&E, coeliac screening, urinalysis for blood and protein, etc.
   

Investigations related to disorders of gonadal axis

• Chromosomes (e.g. for Turner’s and Klinefelter’s syndrome)
• Basal FSH and LH and serum oestradiol/testosterone•
• elvic ultrasound in girls
• GnRH test
• Serum testosterone 4 days after hCG 100 units/Kg (max 1500 units)
• Sense of smell.
   

Diagnosis

• Almost all boys and most girls have CDGA
• The cause of pubertal delay or impairment may be obvious (e.g. ovarian failure following total body irradiation prior to bone marrow transplantation, bilateral neonatal testicular torsion)
• Beware occult chronic disease (e.g. Crohn’s, coeliac)
• Girls with pubertal delay may have primary ovarian failure (e.g. Turner’s syndrome, pure gonadal dysgenesis
• Primary amennorrhoea may be the presenting symptom of Complete Androgen Insensitivity Syndrome (CAIS)

Management of delayed and abnormal puberty

CDGA

• Reassurance
• Height prediction using single observer for bone age
• In boys short course of testosterone therapy

Chronic disease
Treat underlying cause if possible; testosterone/oestrogen treatment is second best

Primary testicular and ovarian failure

• Pubertal induction and hormone replacement thereafter in severe cases (e.g. Turner’s syndrome); if testosterone/oestrogen production is reasonable then treatment may not be necessary
• Counselling with respect to sexual function and fertility

Central delay
If there is known impairment of axis (e.g. due to tumour such as craniopharyngioma) then treatment is obviously required
Some cases of central delay are difficult to assess – the GnRH test cannot distinguish between physiological delay and gonadotrophin deficiency. In doubtful cases it is better to treat, being prepared to stop and re-evaluate axis later, rather than wait indefinitely.

Treatment regimes

CGDA in boys

• Aged 11.5–13.5 years, oxandrolone 1.25–2.5mg at night for 3–6 months may be helpful in maintaining a reasonable height velocity
• Aged >13.5 years of age, testosterone therapy may be offered. This can be given as Sustanon 100mg intramuscularly once a month for 3 months, or as testosterone undecanoate 40mg orally daily for 3 months.
   

CDGA in girls

Oestrogen treatment is best avoided for fear of hastening epiphyseal fusion. If puberty very delayed and growth rate very slow:

• Measure growth hormone levels
• Daily ethinyloestradiol 2?g for a 1–2-year period
• Concurrent growth hormone administration if stimulation testing shows growth hormone insufficiency

Pubertal induction and hormone replacement – boys
There are various regimes that can be used. At Yorkhill the following regime has been effective:

• Sustanon 100 mg every 6 weeks for the first year.
• Sustanon 100 mg every 4 weeks for the second year.
• Sustanon 250 mg every 4 weeks for the third year, then 250-500 mg every 3-4 weeks depending on clinical factors and serum testosterone levels.
• Alternatives include oral testosterone (e.g. testosterone undecanoate 40mg/day for the first year, 80mg/day for the second year and 120mg/day thereafter), testosterone patches, gel, and buccal pellets.
   

Pubertal induction and hormone replacement – girls

Oestrogen replacement should be gradual, not only to avoid premature fusion of the epiphyses, but also to prevent unsightly overdevelopment of the areolae of the breast. We use the following regimens:

• Ethinyloestradiol 2?g/day for 1 year followed by 4?g /day for a further year.
• Ethinyloestradiol 6, 8 and 10?g /day during the third year, in 4-monthly steps.
• Norethisterone 5mg/day for the first 5 days of each.
  calendar month once the ethinylestradiol dosage reaches 10?g /day, or sooner if breakthrough bleeding occurs.
• Low-dose combined contraceptive pill, e.g. Loestrin 20 (21 days on and 7 days off) during fourth year.
  

Table: Classification of delayed and abnormal puberty (including delayed/absent menarche).

Central (both sexes)            Intact H–P axis CDGA                          Chronic systemic disease Poor nutrition (including anorexia nervosa) Psychosocial deprivation Steroid therapy Hypothyroidism   Impaired H–P axis   Tumours adjacent to H–P axis           -Craniopharyngioma -Optic glioma -Germinomas, astrocytomas     Congenital anomalies       -Septo-optic dysplasia -Congenital panhypopituitarism     Irradiation       -Pituitary tumour/optic glioma -Craniospinal axis for medulloblastoma     Trauma       -Surgery, e.g. for craniopharyngioma -Head injury     GnRH/LH/FSH deficiency       -Congenital idiopathic - Kallmann’s syndrome -Prader–Willi syndrome -Laurence–Moon–Bardet–Biedl syndrome Peripheral     Boys Girls       Bilateral testicular damage Gonadal dysgenesis       -Cryptorchidism -Failed orchidopexy -Atresia -Torsion       -Turner’s syndrome -Pure gonadal dysgenesis     Syndromes associated with cryptorchidism Irradiation/chemotherapy       -Noonan’s -Prader–Willi -Laurence–Moon–Bardet–Biedl   -Abdominal irradiation -(for Wilms’ tumour) -Total body irradiation -Cyclophosphamide, busulphan     Gonadal dysgenesis Intersex disorders       -Klinefelter’s -Other XY aneuploidy syndromes -XO/XY   -CAIS -CAH Polycystic ovary syndrome     Irradiation/chemotherapy Toxic damage       Testicular irradiation Total body irradiation Cyclophosphamide     -Galactosaemia -Iron overload (thalassaemia) Abbreviations: CAIS, complete androgen insensitivity syndrome; CDGA, constitutional delay in growth and adolescence; FSH, follicle-stimulating hormone; GnRH, gonadotrophin-releasing hormone; H–P, hypothalamo–pituitary; LH, luteinizing hormone.

Revised: 16-Sep-2005