Approach

Recombinant human growth hormone (rhGH), also known as somatropin, has revolutionised the treatment of growth hormone deficiency (GHD). Crude pituitary extracts were discontinued after association with Creutzfeldt-Jakob disease (CJD).[58]

The decision to treat a patient with GHD should be undertaken after taking into consideration the growth data, insulin-like growth factor 1 (IGF1) and its binding protein (IGFBP3) concentrations, results of the peak GH concentrations after two provocation tests, neuroradiological findings, and the child/family preferences. Early diagnosis and treatment enables normal growth to proceed.

Recombinant human growth hormone (rhGH)

Patients are treated with subcutaneous rhGH given at bedtime to mimic physiological GH release.[42] A rapid short-term growth is followed by normalisation of long-term growth. Treatment should be continued until final height or epiphyseal closure is achieved.[59] A good predictor of response to treatment is the first-year height gain. Other factors include age and height at the start of treatment, and duration of treatment.[60] Studies have also suggested a role for GH receptor and IGFBP3 polymorphisms in determining the growth response, posing challenges in determining an optimal dosing regimen.[61]

In patients with isolated GHD on rhGH treatment, an optimum pre-pubertal growth best determines final height.[23] Treating pubertal GHD patients with a double dose of GH does not increase growth velocity.[62] However, some studies have shown a net increase of 4.6 cm to 5.7 cm in the near-adult final height using higher doses as opposed to lower doses during puberty.[63] Overall, a routine increase in the dose of GH at puberty is not recommended unless the predicted adult height is low, because a high dose can exacerbate physiological hyperinsulinaemia at puberty.[42] Delaying puberty with gonadotrophin-releasing hormone (GnRH) agonists has been attempted as adjunctive therapy to promote the final height, with only a modest increase in height achieved.[64][65]

In the event of persisting hypoglycaemia, rhGH can be commenced during the neonatal period. GH treatment can contribute to hypoglycaemia recovery and may improve cholestasis during the neonatal period.[66] Neonates with isolated GHD (IGHD) or combined pituitary hormone deficiencies (CPHD) will require long-term follow-up to detect early evolving endocrinopathies and optimise treatment.

The recommended starting dose of rhGH varies and depends on the brand and formulation used. The dose is titrated against IGF1 concentrations which should be kept within the normal range.​[42][67]​​ Lower doses can lead to excellent responses. Ongoing treatment is individualised via monitoring of IGF1 concentrations (at least every 3 months initially after treatment has been commenced).

rhGH is safe and well tolerated. There is no risk of CJD. Adverse effects include benign intracranial hypertension, progression of scoliosis, salt and water retention, acute pancreatitis, and slipped capital femoral epiphysis. Thyroid function tests should be regularly monitored because hypothyroidism may be unmasked by treatment.[68] GH treatment also results in an increase in conversion of cortisol to cortisone. Therefore, patients with combined pituitary hormone deficiencies (CPHD) on multiple hormone replacements may need an adjustment in the dose. There is an increased risk of hyperinsulinaemia and type 2 diabetes mellitus, particularly in those with risk factors.[42][69]

The long-term safety of GH treatment in adulthood is, however, uncertain.[70] Patients treated with high doses of pituitary GH given 2 to 3 times/week, with possibly high concentrations of IGF1, have a higher incidence of colonic cancer and Hodgkin's disease.[71] Markedly elevated IGF1 concentrations have been associated with colon, breast, and prostatic cancer.[72][73][74][75][76] However, there is no evidence to suggest an increased risk of malignancies above that of the general population in patients without other risk factors, or tumour progression/recurrence in patients successfully treated for their primary lesion using the current dosage recommendations for rhGH.[42][44] rhGH replacement therapy may marginally hasten the development of secondary neoplasms in childhood cancer survivors (particularly post-irradiation, which in itself is a risk), without increasing the overall incidence.[42][44] In general, GH should not be given with an active malignant condition. Current recommendations, based on widespread clinical practice, are that treatment should only be commenced after waiting 12 months from the end of oncological treatment, with the exception of craniopharyngiomas and optic pathway gliomas when stable disease rather than tumour resolution may often be the aim.[42][44]

Treatment of other pituitary hormone deficiencies

Confirmation of the diagnosis of GHD requires a full pituitary evaluation to rule out other anterior and/or posterior pituitary hormone dysfunction.

  • Thyroid-stimulating hormone deficiency should be treated with levothyroxine.

  • Adrenocorticotrophic hormone (ACTH) deficiency should be treated with glucocorticoid treatment. These patients do not require treatment with mineralocorticoids, as they are not regulated by ACTH. Glucocorticoid replacement may unmask arginine vasopressin deficiency (central diabetes insipidus).

  • Central precocious puberty can be treated with GnRH analogues.

  • Gonadotrophin deficiency should be treated with oestrogen in girls (eventually adding in progesterone) and with testosterone in boys. Common practice is to delay pubertal induction for at least 6 months after commencing GH replacement to optimise adult height.

  • Arginine vasopressin deficiency (central diabetes insipidus) is treated with desmopressin therapy.

There are no known deleterious effects of prolactin or oxytocin deficiency in children.

Treatment of underlying cause

GHD in patients with central nervous system (CNS) tumours can already be present at diagnosis with sellar/suprasellar lesions, or after radiotherapy/surgery (i.e., following definitive treatment). If short stature and GHD lead to a diagnosis of a CNS tumour, urgent neurosurgical and neuro-oncological referral should be sought. Tumour marker tests (prolactin, alpha-fetoprotein, beta-human chorionic gonadotrophin) should be performed prior to definitive treatment in all patients with sellar/suprasellar lesions to exclude the diagnosis of a prolactinoma and germ cell tumour, respectively, which may not require immediate neurosurgical intervention.

Optimisation of blood transfusion/chelation therapy may be required in patients who develop GHD due to iron overload, although this complication is not typically reversible.

Patients with eye abnormalities should be referred to an ophthalmologist to detect optic nerve hypoplasia or a suprasellar space-occupying lesion pressing on the optic chiasm/nerves.

Psychosocial causes of GHD need to be treated as appropriate, because the GHD is entirely reversible and would not respond as well to rhGH.

Transition to adult care

A planned transition to adult care is important for children with GHD to reduce the risk of them disengaging with follow-up care. Clinicians should start counselling patients and their parents well in advance of the transition period and should collaborate with adult endocrine services to ensure a seamless transfer.[77]

Adolescents who have achieved their final height but have confirmed persistent GHD should resume rhGH replacement therapy because of long-term benefits including bone health, quality of life, body composition, and lipid metabolism. Those who do not have persistent GHD into adulthood still require long-term surveillance.[77]

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