Approach

Recombinant human growth hormone (rhGH), also known as somatropin, has revolutionized the treatment of GHD. Crude pituitary extracts were discontinued after association with Creutzfeldt-Jakob disease (CJD).[58] rhGH has also been used in Turner syndrome, intrauterine growth restriction (IUGR), chronic renal failure, Prader-Willi syndrome, idiopathic short stature, and SHOX deficiency.[59][60]

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, neuroradiologic 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.[42] A rapid short-term growth is followed by a normalization of long-term growth. Treatment should be continued until final height or epiphyseal closure is achieved.[61] 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.[62] 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.[63]

In patients with isolated GHD on rhGH treatment, an optimum prepubertal growth best determines the final height.[23] Treating pubertal GHD patients with a double dose of GH does not increase the growth velocity.[64] However, some studies have shown a net increase of 4.6 to 5.7 cm in the near-adult final height using higher doses as opposed to lower doses during puberty.[65] Overall, a routine increase in the dose of GH at puberty is not recommended unless the predicted adult height is poor because a high dose can exacerbate the physiologic hyperinsulinemia at puberty.[42] Delaying puberty with gonadotropin-releasing hormone (GnRH) agonists has been attempted as adjunctive therapy to promote the final height, with only a modest increase in height achieved.[66][67]

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 hyperinsulinemia 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 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 tumor 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 oncologic treatment, with the exception of craniopharyngiomas and optic pathway gliomas when stable disease rather than tumor 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.

  • Adrenocorticotropic 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 diabetes insipidus.

  • Central precocious puberty can be treated with GnRH analogs.

  • Gonadotropin deficiency should be treated with estrogen in girls (eventually adding in progesterone) and with testosterone in boys.

  • Diabetes insipidus is treated with desmopressin (DDAVP) 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) tumors can already be present at diagnosis with sellar/suprasellar lesions, or after radiation therapy/surgery (i.e., following definitive treatment). If short stature and GHD leads to a diagnosis of a CNS tumor, urgent neurosurgical and neuro-oncologic referral should be sought. Tumor marker tests (prolactin, alpha-fetoprotein, beta-human chorionic gonadotropin) should be performed prior to definitive treatment in all patients with sellar/suprasellar lesions to exclude the diagnosis of a prolactinoma and germinoma, respectively, which may not require immediate neurosurgical intervention.

Optimization 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 counseling patients and their parents well in advance of the transition period and should collaborate with adult endocrine services to ensure a seamless transfer.[57]

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.[57]

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