Growth hormone deficiency medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Medical Therapy

Children treatment

Indications 10-13

• Treatment with GH is indicated for children with GH deficiency whose epiphyses are open.
• Treatment should be continued until linear growth ceases or even beyond.

Dosing

• The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections.
• The dose for patients with severe GH deficiency is 20 micrograms/kg/day.

Dosing during puberty 

• A temporary increase in GH dose (eg, to 70 to 100 micrograms/kg/day) has been suggested in case of failed proper response to treatment. [21]
• Although, effective treatment with GH prior to puberty is more efficacious and cost-effective than efforts to boost growth during puberty.

Monitoring 

• Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment.
• This helps to avoid very high IGF-I levels, which are thought to be associated with some of the drug's toxicity.
• as recommended in guidelines from the Pediatric Endocrine Society (PES) [14]:

• If the IGF-I level is below this target range, increase the dose of GH because GH is unlikely to be efficacious if IGF-I levels are very low.
• If the IGF-I level is above this target range (ie, >+2 SD), we reduce the GH dose to prevent GH toxicity.
• For patients with multiple pituitary hormone deficiencies, adrenal and thyroid function should be reassessed a few months after initiation of GH therapy and periodically by measuring 8 to 9 AM serum cortisol and free T4, respectively [14]

Duration of therapy 

Treatment is continued at least until linear growth decreases to less than 2.0 to 2.5 cm (0.8 to 1 inch)/year [14].

More than two-thirds of patients have normal results when retested for GH deficiency as adults.

It is important to repeat the GH stimulation test during the transition period to determine if they will require ongoing therapy.

GH deficiency is usually permanent in patients with genetic causes of GH deficiency (recognized by a family history of GH deficiency), structural causes of GH deficiency (eg, optic nerve hypoplasia), or organic GH deficiency (eg, caused by brain surgery, brain tumors, intracranial irradiation, or associated with multiple pituitary hormone deficiencies).

Growth response to GH therapy 

if GH is administered at an early age, patients can achieve adult height within the midparental target height range [17,18].

recheck length or height at least every four to six months and calculate the height velocity to determine whether the growth response is adequate (algorithm 1)

During the initial "catch-up" growth period, the 75^th percentile curve for height velocity is an appropriate target to define an adequate growth response to GH.

Catch-up growth should continue until the child's height percentile is in the expected range Children who have an inadequate growth response to GH therapy should be reevaluated. The causes can be categorized by the IGF-I level

IGF-I level below target range 

Poor adherence to GH treatment or a technical issue in its administration.

Sub-therapeutic dose of GH.

The patient has GH deficiency, but has concurrent mild GH insensitivity.

Development of neutralizing antibodies to GH – Patients who develop neutralizing antibodies to GH tend to have an initial typical growth response to GH treatment over the first three to six months, and then suddenly have a diminution of their growth rate, with low levels of IGF-I despite adequate dosing of GH, reflecting acquired GH insensitivity. This problem may occur in patients with GH deficiency due to a GH1 gene deletion (also referred to as isolated GH deficiency type IA,

The diagnosis is supported by serum testing for antihuman GH antibodies, and/or by genetic testing to determine whether the patient's GH deficiency is caused by a GH gene deletion. These patients respond favorably to treatment with recombinant human IGF-I (mecasermin).

IGF-I level variable

IGF-I levels vary depending on the patient's nutritional status, but usually are below the normal range or in the low end of the normal range

Development of central hypothyroidism

Patients with multiple pituitary hormone deficiencies are at risk for treatment-emergent hypothyroidism because GH enhances conversion of thyroxine (T4) to triiodothyronine (T3).

The patient has comorbid disease that limits growth (eg, inflammatory bowel disease or untreated celiac disease).

OUTCOMES OF GROWTH HORMONE THERAPY

Growth 

better response to GH therapy were younger age at start of GH treatment

greater bone age delay at initiation of therapy, and more severe GH deficiency [23]

Bone mass 

Children with GH deficiency have low bone mass compared with age- and size-matched control children.

To maximize peak bone mass, it is important to consider the continuation of GH treatment even after linear growth has ceased until full skeletal   [24].

These findings suggest that GH therapy increases bone mass and the progression toward peak bone mass [26]. Without adequate GH replacement, either childhood- or adult-onset GH deficiency can be associated with low bone mass during adulthood  27,28

ADVERSE EFFECTS OF GROWTH HORMONE THERAPY 

Treatment of children with recombinant human GH has generally been safe [29-31].

Acute effects 

• Headaches which usually are benign.
• Idiopathic intracranial hypertension (formerly known as pseudotumor cerebri), increased intraocular pressure [32] usually resolves with discontinuation of GH therapy. Treatment can often be resumed at a lower dose without return of symptoms back up to standard doses.
• Slipped capital femoral epiphysis [33] routine monitoring is recommended for suggestive symptoms such as hip and/or knee pain, and changes in gait. This condition usually requires surgical pinning of the capital femoral epiphysis.
• Worsening of existing scoliosis [29]
• Pancreatitis
• Gynecomastia
• increase in the growth and pigmentation of nevi, without malignant degeneration [29,34]
• Carpal tunnel syndrome, edema, and arthralgia are more common in adults undergoing GH treatment but are unusual in children.
• Most usually occur soon after therapy is initiated, and some of these effects are probably caused by sodium and water retention [35]. Rarely, a child treated with GH develops neutralizing antibodies, resulting in loss of efficacy [36,37].
• Development of insulin resistance and disorders of glucose intolerance may occur in children receiving GH therapy (especially those with predisposing conditions, eg, Prader Willi syndrome), but the overall clinical significance appears to be low. An international surveillance program of 23,333 children and adolescents receiving GH identified 18 new cases of type 2 diabetes mellitus and 14 of impaired glucose tolerance [38]. Although these numbers were higher than expected as compared with historical controls, the number of patients affected is small. The incidence of type 1 diabetes mellitus is not increased by GH therapy.

Cronic effects

Concerns have been raised about a possible role for GH or its mediator insulin-like growth factor-I (IGF-I) in cancer risk; these concerns are primarily based on observations that higher IGF-I levels in normal individuals are associated with increased risks for breast or prostate cancer [39].

Several observational studies have attempted to determine whether GH treatment affects cancer risk. Although there is some disagreement among studies, the preponderance of data leads to the following conclusions:

For patients with isolated growth failure (isolated GH deficiency, idiopathic short stature, or prenatal growth failure) and no other risk factors, GH therapy does not increase the risk for leukemia or other cancers compared with the age-matched general population. The best information comes from the Safety and Appropriateness of GH treatments in Europe (SAGhE) study, which followed almost 24,000 patients, approximately one-half of whom had isolated growth failure [40]. In long-term follow-up, the patients with isolated growth failure had no overall increase in cancer risk (Standardized Incidence Ratio [SIR] 1.0; 95% CI 0.6-1.4) or cancer mortality. The certainty about this conclusion is somewhat limited because of the rarity of cancer in this cohort (23 cases among 11,062 treated subjects) and limited length of follow-up (mean 14.8 years per patient). However, a lack of association with cancer was also found in prior studies with shorter length of follow-up [41-45], including some that focused primarily on leukemia [46-48].

For patients with a primary cancer diagnosis that led to the GH treatment, recombinant GH was associated with a modest increase in risk for a secondary cancer (SIR 7.6, 95% CI 6.1-9.6) [40]. The increased risk was significant for a variety of secondary cancers including bone, melanoma, kidney, brain, thyroid, and leukemia. Cancer mortality increased with GH dose and duration of treatment. Since childhood cancer patients are known to be at increased risk for secondary cancers, due to the underlying cancer itself and/or cancer-directed therapy (especially radiation), the increased incidence of secondary cancers among these patients may or may not be related to the GH treatment.

Prior smaller studies of childhood cancer survivors who had been treated with GH noted little or no increased risk for secondary malignancy, except for the development of benign meningiomas after radiation treatment of certain primary brain tumors [49-52].

For patients with other non-cancer primary diagnoses that led to GH treatment (eg, Turner syndrome or hypopituitarism without cancer), there was a modest increase in cancer risk (SIR 1.4, 95% CI 1.1-1.9), primarily due to an excess of bone or bladder cancer, although based on small numbers for each site [40].

For children with cancer (including craniopharyngioma) who develop GH deficiency, guidelines suggest a 12-month waiting period after completion of cancer-directed therapy to confirm that the cancer was eradicated before initiating GH therapy [14].

Treatment protocol 

• GH is administered by subcutaneous injection once a day, usually in the evening.
• The initial goal is to start with a lower than maintenance dose and to gradually increase the dose (to minimize side effects).
• The starting dose should be 2 to 5 mcg/kg body weight once daily toward the lower end of the range for men, women taking estrogen transdermally, and those over age 60 years, and the upper end for women taking estrogen orally. This weight-based recommendation is for the starting dose only. The goal should be to start with low doses and increase gradually until the serum IGF-1 concentration is normal.
• The eventual goal is to find the GH dose that maintains the serum IGF-1 concentration within the middle of the age-adjusted normal range [4]. [26]

• If the serum IGF-1 concentration has not increased to within the normal range after two months, the daily dose should be increased stepwise in 1 to 2 mcg/kg increments at two-month intervals until it is normal. A dose of greater than 10 to 12 mcg/kg is not likely to be needed.
• If side effects occur or the serum IGF-1 concentration increases to above normal at any dose, the dose should be decreased.

Duration of therapy

• recommend continuing treatment indefinitely.
• A systematic review of 23 studies of long-term GH therapy suggests that it may have some sustained benefits for body composition, lipid profile, carotid intima media thickness, and BMD but not for muscle strength [62]. [63]
• Stopping the treatment causes an increase in C-reactive protein and increases in both LDL and HDL cholesterol but improved insulin sensitivity and decreased glycated hemoglobin (A1C).

Monitoring 

• Measurement of serum IGF-1 is probably the best single test of the adequacy of GH treatment [64].
• GH treatment should increase the serum IGF-1 concentration to within, but not higher than, the age-specific range of normal to avoid over replacement.
• We suggest measuring a serum IGF-1 two months after starting therapy.
• if the serum concentration is below the normal age-specific range, the daily GH dose should be increased stepwise in 1 to 2 mcg increments at two-month intervals until it is within the normal range.
• Once serum IGF-1 is in the normal range, we suggest repeating it every 6 to 12 months.
• If IGF-1 is ever above normal, the GH dose should be decreased by 1 to 2 mcg/kg increments and serum IGF-1 should be repeated every two months until it returns to the normal range.