Short stature

Short stature is defined by national standards of growth and centile charts, taking into account mid parental height, and is generally accepted as a standing height >2SD below the mean. The commonest causes are familial short stature and constitutional delay of growth. Growth hormone deficiency, GH resistance, hypothyroidism, Turner and Cushing’s syndrome are rarer endocrine causes, and malnutrition remains the commonest cause worldwide.

Familial short stature confirmed

In familial short stature (also referred to as genetic short stature) bone age and growth velocity are normal for chronological age, and adult height is appropriate for the familial pattern.

No treatment is required for this condition.

Constitutional delay of growth

Constitutional growth delay is characterised by delayed bone age, normal growth velocity, and predicted adult height appropriate to the family pattern. This should be regarded as a normal variant and as such does not usually require treatment, though most children and families benefit from reassurance and counselling. However these patients frequently do not reach their parental target, and patients with constitutional growth delay often have a first- or second-degree relative who also had constitutional growth delay.

In boys aged 10-13 years with mild growth delay, treatment with oxandrolone 1.25-2.5mg daily for 6-12 months can be beneficial. Boys aged over 13 years with more severe delay of growth and puberty usually benefit from androgen therapy, i.e. testosterone depot 50-250mg 2-4 weekly for a limited period, usually 4-6 months. GH is not licenced for use in constitutional growth delay, although higher doses may ameliorate growth.

Short stature confirmed

Short stature is confirmed in a child with a standing height of <-2.0 SD for chronological age, sex and ethnic background. A child with a height velocity below the 5th to 10th percentile for age, with no clear aetiology should also be treated as for confirmed short stature. 

Patients with the phenotype of hypothalamic-pituitary dysfunction (eg microphallus, septo-optic dysplasia, tumour in the hypothalamic-pituitary region or history of cranial irradiation) with decelerating growth, and patients with other deficits in their hypothalamic-pituitary hormones require full assessment as for their underlying condition. Their short stature can be treated conventionally depending on their other health issues.

Short stature confirmed without GH deficiency

GH therapy is also used for confirmed short stature associated with other non-GH deficiency causes, with different doses required according to underlying diagnosis and patient response. Excellent guidance is available on Short stature forum.

In Turner syndrome (TS) and Noonan syndrome (not licensed by the EMEA) GH 0.05-0.067mg/kg/day is recommended. In small for gestational age patients GH 0.033 or 0.067mg/kg/day (European dose) may be used.

In Prader-Willi syndrome the recommended dose is 0.05mg/kg/day. In chronic renal failure the recommended dose is 0.08mg/kg/day.

In idiopathic short stature (not licensed by the EMEA) a starting dose of 0.05mg/kg/day is recommended.

Linear growth must be monitored every 6 months during therapy to help with dose titration. Serum IGF-I should also be monitored 6-12 monthly to ensure doses are not excessive, though in paediatrics unlike in adult endocrinology, dose adjustments are not generally guided by IGF-I assessments.

GH deficiency confirmed

Short stature in GHD tends to have and excellent response to GH therapy. GH therapy in a dose of 0.025-0.035mg/kg/day (UK dose) is given in as daily subcutaneous injections in children from the time of diagnosis of GHD until completion of growth after puberty. Some specialists recommend increasing the dose during puberty. 

Recombinant human GH administration increases adult height into the normal range for the population and into the child’s genetic target range provided the treatment is started in early childhood. However, delayed treatment, severity of GHD, IGF-I level, severity of short stature and dose of GH may predict the response in individual patients.

 Primary IGF-I deficiency

Severe primary IGFD, results from genetic defects of GH action, e.g. GH receptor defects, and so does not respond to GH therapy. Recombinant human IGF-1 is licensed and indicated for long-term treatment in this condition as defined by height <-3 SD, IGF-I <-3 SD (FDA, or <2.5th centile EMEA), with normal GH reserve on dynamic testing.

The recommended starting dosage is 40 mcg/kg twice daily SC and must always be given with a meal. The dose should be increased to 80 mcg/kg and then to 120 mcg/kg twice daily within 2-3 months. Preprandial glucose monitoring should be considered at treatment initiation and until a well-tolerated dose is established.

If frequent symptoms of hypoglycaemia occur, preprandial glucose monitoring should continue. If hypoglycaemia occurs with recommended doses, despite adequate food intake, the dose should be reduced.

Adverse effects include hypoglycaemia, lipohypertrophy, and tonsillar hypertrophy, intracranial hypertension with papilloedema may develop and cause visual changes, headache, nausea, or vomiting; rapid growth may cause slipped capital femoral epiphysis and scoliosis progression; protein substance administration may cause local or systemic reaction (e.g. flushing, hypotension/hypertension, rash, dyspnoea).

Linear growth must be monitored every 6 months to ensure adequate therapeutic response.

Absent puberty (any cause)

Discuss treatment aims, timescales and outcomes

Treatment aims to replicate the natural process of puberty and should occur over approximately the same timescale - approximately two to three years.

Adult patients should be warned that accelerating the process may have adverse long term psychological and physical consequences, for example poor breast development.

Discuss fertility issues at, or soon after, diagnosis

If appropriate, fertility should be discussed early with the patient and their family.

Patients need to understand that successful pubertal induction will not affect or restore fertility, although appropriate uterine development is necessary prior to possible future pregnancies.

Karyotype analysis

Adult patients with absent puberty require karyotype analysis to differentiate between different causes, for example Klinefelter's syndrome, androgen insensitivity or Turner's syndrome.

Review baseline pituitary function

If there is any doubt that hypogonadotropic hypogonadism may not be isolated, consider dynamic function testing.

MRI pituitary

If karyotype is normal, and cause of hypogonadotropic hypogonadism is uncertain, thorough investigation for other causes should be performed.

Consider assessing bone age

Delayed bone age supports the diagnosis of absent puberty.

Initiate treatment: females

Initiate very low dose estrogen replacement therapy.

Typical starting dose in an estrogen naive patient is 1.25mcg ethinylestradiol. Increase dose to 2.5mcg, then by 2.5mcg increments every six months to 10mcg. The dose may then increase to 15mcg.

Dose titration

Consider pelvic ultrasound scan to assess uterine size at this stage.

Once the patient experiences vaginal bleeding or if the patient has tolerated 15mcg, consider adding cyclical progesterone.

Alternative treatment regimens

Cyclical estrogen and progesterone replacement therapy should be considered in all patients.

The combined oral contraceptive pill is a convenient preparation and may be more socially acceptable at diagnosis and in young patients. However, there has been some doubt as to whether this offers sufficient bony protection unless taken continuously, with some authorities advising taking this 3 packs at a time. Combined oral contraceptive pills are also contraindicated in patients with a history of migraines with aura. Low dose HRT is more suitable in these cases.

Hormone replacement therapy is more appropriate in the long term, and should be tailored to suit the individual, for example by offering topical, depot or oral preparations. Choice will also depend on the age of the patient, presence or absence of a uterus, and history or family history of breast or endometrial cancer. A history of, or strong risk factors for cardiovascular or thromboembolic disease will also need to be considered.

Topical estrogen is particularly useful in patients at high cardiovascular risk, or with abnormalities of liver function. Combined patches are available, or if estrogen gel is used, low dose continuous progesterone will also be required to prevent endometrial hyperplasia eg 1x350mcg progesterone only pill daily.

Estrogen replacement therapy should be continued until the time of the natural menopause - typically to age 50. Vaginal dryness may be ameliorated by topical estrogen gels.

Duration of treatment

Continue sex hormone replacement therapy until the time of the natural menopause - typically to age 50.

Follow up

Offer life long follow up to all patients.

Consider periodic monitoring of bone densitometry and of pituitary function where indicated.

Patients with Turner syndrome, Klinefelter’s, Kallmann’s or underlying pituitary disease will require specific follow up.

Initiate treatment: male patients

Initiate very low dose testosterone therapy, and warn patient of expected psychological and physical effects.

Typical starting dose in a testosterone naive patient is approximately 20% of the usual adult dose. This has traditionally been given as 50mg testosterone ester as an intramuscular injection, monthly, though an alternative is to use very low dose daily testosterone gel using a metered dose delivery system.

Dose titration

Monthly testosterone treatment is then typically increased by a further 50mg every six months according to clinical response.

Alternatives include low dose depot testosterone, or topical gel using the same dosing schedule.

Treatment monitoring

Routine monitoring of serum testosterone levels is not necessary until the expected adult dose is reached.

Peak and trough levels may then be useful to confirm the appropriateness of the final dose in patients taking monthly testosterone undecanoate. Peak 7 days post injection should typically be 25-30nmol/l, with a predose trough level of 8-12nmol/l. Subsequently, the dose should not be altered unless the clinical response is suboptimal, or in the light of changes in serum monitoring of prostate specific antigen, full blood count, liver function, or pre dose testosterone levels.

In patients taking depot preparations, a random or pre dose level of 15-20nmol/l, and for patients taking daily topical preparations, a level of 15-20nmol/l 4-6 hours post application of the gel is usually sufficient.

Alternative treatments

Once patient is virilised appropriately and established on full adult dose, offer switching to alternative preparation, for example daily gel or depot preparation.

Optimise final dose according to symptoms and serum levels.

Annual monitoring

Annual random levels are sufficient in patients on topical and depot preparations. Annual pre dose levels are required in those on injectable testosterone esters. 

Digital rectal examination, prostate specific antigen, full blood count and liver function tests should also be performed annually with dose reduction and onward referral if abnormalities arise.

Follow up

Offer life long follow up to all patients.

Consider periodic monitoring of bone densitometry and of pituitary function where indicated.

Patients with Turner’s syndrome, Klinefelter’s, Kallmann’s or underlying pituitary disease will require specific follow up.

Turner syndrome

Offer genetic counselling. Follow the treatment pathway for pubertal induction. 

For further management see Turner syndrome.