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Treatment of growth hormone deficiency in children

Treatment of growth hormone deficiency in children
Literature review current through: Jan 2024.
This topic last updated: Jul 20, 2023.

INTRODUCTION — Recombinant human growth hormone (rhGH) is the primary treatment for growth hormone (GH) deficiency-induced short stature, as well as the associated abnormalities in body composition, metabolic profile, exercise capacity, and quality of life [1]. Challenges to effective treatment include difficulty in establishing a firm diagnosis of GH deficiency and variable responsiveness to rhGH within the population diagnosed with GH deficiency.

The indications for and efficacy of exogenous rhGH treatment in children with GH deficiency are reviewed here. The diagnostic approach to the child with short stature and the diagnosis of GH deficiency are discussed separately. (See "Causes of short stature" and "Diagnostic approach to children and adolescents with short stature" and "Diagnosis of growth hormone deficiency in children".)

rhGH therapy is also prescribed for several other specific indications in children and adolescents, including idiopathic short stature and short stature associated with small for gestational age (SGA), chronic kidney disease, Turner syndrome, Prader-Willi syndrome, mutations in the SHOX gene, and Noonan syndrome. These uses are discussed in separate topic reviews:

(See "Growth hormone treatment for idiopathic short stature".)

(See "Growth hormone treatment for children born small for gestational age".)

(See "Growth failure in children with chronic kidney disease: Treatment with growth hormone".)

(See "Management of Turner syndrome in children and adolescents".)

(See "Prader-Willi syndrome: Management".)

(See "Causes of short stature", section on 'SHOX gene variants'.)

(See "Causes of short stature", section on 'Noonan syndrome'.)

PHYSIOLOGIC ACTIONS OF GROWTH HORMONE — GH affects many of the metabolic processes carried out by somatic cells. The best known is the effect of increasing body mass. Although GH stimulates generalized growth, it is not evenly distributed among the protein, lipid, and carbohydrate compartments. GH increases total body protein content, decreases total body fat content, and increases fat deposition in the liver. Physiologic concentrations of GH also have beneficial effects on the plasma lipid profile (ie, decreases serum low-density lipoprotein and increases high-density lipoprotein), although either GH deficiency or excess may be associated with dyslipidemia and the plasma lipid profile may fluctuate acutely during replacement therapy with recombinant human growth hormone (rhGH) [2-4]. The effects on fat are due to stimulation of lipolysis and reciprocal antagonism of the lipogenic action of insulin in peripheral fat stores.

GH also increases bone mass by stimulating skeletal insulin-like growth factor 1 (IGF-1) synthesis and causing proliferation of prechondrocytes, hypertrophy of osteoblasts, bone remodeling, and net mineralization [5]. GH stimulates cartilage growth. This is most evident as a widening of the epiphyseal plate and is associated with an increase in amino acid incorporation into cartilage and bone [6]. GH also stimulates the uptake of sulfate by cartilage in vivo but not in vitro. However, in vitro sulfate uptake is stimulated by serum from normal or hypophysectomized animals treated with GH. This "sulfation factor" proved to be IGF-1 [7,8]. (See "Physiology of insulin-like growth factor 1".)

DIAGNOSIS OF GROWTH HORMONE DEFICIENCY — GH deficiency is a clinical diagnosis based on auxologic features (ie, a comparison of a child's growth pattern to established norms) and confirmed by biochemical testing. Once the decision has been made to evaluate a short child for GH deficiency, several different tests can be performed. (See "Diagnosis of growth hormone deficiency in children".)

If GH deficiency is congenital and complete, the diagnosis is relatively easy to confirm. Affected children present with early severe growth failure; delayed bone age (if the diagnosis is significantly delayed); central distribution of body fat; and very low serum concentrations of GH, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 3 (IGFBP-3), the major binding protein of circulating IGF-1 [9]. Infants with GH deficiency are prone to hypoglycemia, prolonged jaundice, microphallus (in males), and giant-cell hepatitis. If hypoglycemia is noted, treatment with recombinant human growth hormone (rhGH) should be initiated expeditiously to protect against further episodes.

For children with milder manifestations of GH deficiency, it may be more difficult to establish the diagnosis. Nonetheless, once the diagnosis is confirmed, such children can and should be treated with rhGH until linear growth ceases. (See 'Growth hormone treatment' below and 'Duration of therapy' below.)

GROWTH HORMONE TREATMENT

Indications — Treatment with recombinant human growth hormone (rhGH) is appropriate for children with GH deficiency whose epiphyses are open. The growth response is greater when rhGH is initiated at younger versus older age. Therefore, treatment should be initiated as soon as the diagnosis is confirmed and continued until linear growth ceases.

Formulations of growth hormone — Several brands of recombinant human growth hormone (rhGH) are approved for treatment of GH deficiency in children, and others are being tested:

Once-daily formulations – Most children with GH deficiency are treated with aqueous biosynthetic recombinant human growth hormone, which is administered by subcutaneous injection (usually daily). Several brands of rhGH have been available for subcutaneous administration for many years, and most information about rhGH treatment comes from these preparations. They are equally biopotent and have the same natural sequence structure as endogenous human GH. Most are available in multiple-dose pen devices that facilitate administration.

Long-acting formulations – There are two varieties of long-acting rhGH formulations: sustained-release preparations of rhGH, and analogues of rhGH with additional peptides or fatty acids or bound to larger molecules [10,11]:

Lonapegsomatropin (once-weekly) is a sustained-release preparation of rhGH approved in the United States is for children with GH deficiency one year of age and older and weighing at least 11.5 kg [12]. It is a prodrug of somatropin that provides sustained release of active, unmodified somatropin [13]. In a 52-week randomized trial, lonapegsomatropin injected subcutaneously once weekly achieved a similar annualized height velocity (11.2±0.2 cm/year) compared with equivalent doses of aqueous rhGH administered by daily subcutaneous injection of rhGH (10.3±0.3 cm/year) [14]. Estimated average insulin-like growth factor 1 (IGF-1) concentrations were slightly higher for lonapegsomatropin compared with daily rhGH but remained within the normal range, although IGF-1 values in individual participants occasionally exceeded +2 standard deviations (SD) at some point in the trial (7.6 percent of measurements for lonapegsomatropin and 3.6 percent of measurements for daily rhGH). This study did not detect any differences in tolerability or short-term side effects.

Somapacitan (once-weekly) is a long-acting rhGH analog approved in the United States for children ages 2.5 years and older with growth failure due to GH deficiency [15]. A single amino acid substitution and a long fatty acid moiety permit a noncovalent association with circulating albumin, thereby extending the half-life of the molecule in the circulation. In a 52-week randomized phase 3 trial in 200 children, height velocity was similar in participants treated with somapacitan (0.16 mg/kg/week) compared with once-daily aqueous rhGH (0.24 mg/kg/week), with similar safety signals and tolerability [16]. Mean IGF-1 levels remained within the normal range at one and three years [17].

Somatrogon (once-weekly) is a long-acting rhGH analog that is now approved in most countries including the United States [18-20]. It contains the amino acid sequence of hGH and three copies of the C-terminal peptide (CTP) of human chorionic gonadotropin (hCG) to form a fusion protein. The inclusion of CTP in proteins leads to increased half-life. In a 12-month phase 3 trial, height velocity was similar in participants treated with once-weekly somatrogon (0.66 mg/kg/week) compared with once-daily aqueous rhGH (0.24 mg/kg/week), with similar safety signals and tolerability [18]. The estimated average IGF-1 concentration was within the normal range for both groups (approximately +0.6 SD for somatrogon and -0.7 SD for daily rhGH); in the somatrogon group, 1.9 percent of samples corresponded to a mean IGF-1 concentration >+2 SD.

Initial dosing — The usual dosing of rhGH for childhood GH deficiency depends on the formulation:

For standard recombinant human growth hormone (somatropin), the starting dose is between 0.16 and 0.24 mg/kg/week, divided into once-daily injections. For most patients, our practice is to start at the upper end of this range (0.24 mg/kg/week, ie, approximately 35 micrograms/kg/day). For patients with severe GH deficiency, we use a lower starting dose of approximately 20 micrograms/kg/day because these individuals have excellent growth responses in this dose range.

For this formulation, daily therapy is more effective than three-times weekly at the same total dose [21,22]. Some experts suggest administering rhGH in the evening, based on the rationale that this more closely mimics the predominance of GH secretion during sleep. However, there is no evidence that this dosing schedule is more effective than any other.

For lonapegsomatropin, approved dosing is 0.24 mg/kg given once weekly (for children ≥1 year with weight ≥11.5 kg) [12].

For somapacitan, the approved dose is 0.16 mg/kg administered once weekly.

For somatrogon (NGENLA), the approved dose is 0.66 mg/kg administered once weekly, subsequently individualized based on growth response [20].

For most patients, we use the once-daily formulation of rhGH. As clinical experience with long-acting GH preparations increases, we anticipate that an increasing proportion of children will be treated with these formulations.

Most endocrinologists adjust the rhGH dose based on growth response, serum insulin-like growth factor 1 (IGF-1) levels, and body weight, as discussed below. (See 'Dose adjustment based on IGF-1 response' below.)

In the United States, one manufacturer obtained approval for rhGH dosing up to 0.70 mg/kg/week during puberty, but guidelines recommend against the routine use of this approach because the safety and efficacy are not established [22]. (See 'Dosing during puberty' below.)

Dose adjustment based on IGF-1 response — Serum levels of IGF-1 should be measured approximately five weeks after beginning rhGH treatment or making a dose adjustment (algorithm 1). The rhGH dose should be lowered if serum IGF-1 levels rise above the normal range, as recommended in guidelines from the Pediatric Endocrine Society (PES) [22]. This helps to avoid very high IGF-1 levels, which may be associated with some of the drug's toxicity. (See 'Adverse effects of growth hormone therapy' below.)

The discussion below refers to an average IGF-1 level. If rhGH is given daily, random sampling is sufficient. If a long-acting rhGH formulation is used, interpretation of an IGF-1 level is more complex and depends on the formulation and timing of the sample compared with the last dose [23]:

For lonapegsomatropin, IGF-1 samples at 4.5 days after the last dose provide a good estimate of the average weekly IGF-1 concentration and could be used to guide dose adjustments, while samples taken on other days require mathematical adjustments to predict average IGF-1 concentrations [24].

For somapacitan, IGF-1 samples collected either two or four days after the last dose provide an estimate of the mean IGF-1 [25].

For somatrogon, IGF-1 samples collected at approximately 96 hours (four days) after the last dose represent the mean IGF-1 [18].

In our practice, we also use serum IGF-1 levels for further adjustments to the rhGH dose. This "fine-tuning" approach is not endorsed by the PES guidelines, because data on adult height outcomes are not available [22]. However, we choose to use this approach because published intermediate outcomes suggest that IGF-1-based dosing may increase height velocity and is sometimes dose-sparing, presumably because it addresses the variable sensitivity to rhGH therapy among patients [26,27]. However, the most important efficacy outcomes are short-term height velocity and longer-term overall growth, irrespective of the IGF-1 level. Trials of some longer-acting rhGH molecules report height velocity outcomes that appear to be similar to, if not slightly greater than, those seen with daily rhGH preparations [14,17,18,24,25]. Induced IGF-1 levels in these studies are similar to or, in some cases, higher than those seen with daily dosing.

Various protocols are used for IGF-1-based dose adjustment. In our practice, we measure IGF-1 approximately four weeks after beginning rhGH therapy or changing the dose. We target an IGF-1 level in the upper one-half of the normal range (ie, 0 to +2 SD, based on bone age). If the IGF-1 level is below this target range, we increase the dose of rhGH (eg, by 10 to 20 percent) because the treatment is unlikely to be efficacious if IGF-1 levels are very low. If the IGF-1 level is above this target range (ie, >+2 SD), we reduce the rhGH dose (eg, by 10 to 20 percent) because there are some concerns about the safety of high IGF-1 levels. (See 'Adverse effects of growth hormone therapy' below.)

If rhGH is increased to >0.3 mg/week but IGF-1 levels remain low (<-1 SD), the first step is to evaluate for adherence to therapy and proper injection technique and for underlying medical problems that might limit growth. If these problems can be excluded and IGF-1 levels remain low, the patient may have GH insensitivity. If such patients also fail to have a good growth response to rhGH therapy, the possibility of a GH insensitivity syndrome should be explored. (See 'Growth response to recombinant human growth hormone therapy' below and "Growth hormone insensitivity syndromes".)

Ongoing monitoring — For children who achieve IGF-1 target levels in response to rhGH therapy, we continue rhGH at the same dose and monitor the growth response and IGF-1 levels periodically during therapy, as outlined below. After four to six months of treatment, the growth response is a more appropriate benchmark rather than the IGF-1 level.

Growth response to recombinant human growth hormone therapy — When given for the treatment of GH deficiency, rhGH therapy is clearly effective; if rhGH is administered at an early age, patients can achieve adult height within the midparental target height range [28,29].

For children with IGF-1 levels in the target range, we recheck length or height at least every four to six months (or every two to three months in infants) and calculate the height velocity to determine whether the growth response is adequate (algorithm 1).

The child's height velocity should be compared with curves showing normal height velocity for age in children without GH deficiency (figure 1A-B). During the initial "catch-up" growth period, the 75th percentile curve for height velocity is an appropriate target to define an adequate growth response to rhGH. Catch-up growth should continue until the child's height percentile is in the expected range (eg, at the height percentile corresponding to the midparental height). (See "Diagnostic approach to children and adolescents with short stature", section on 'Is the child's height velocity impaired?'.)

Children who have an inadequate growth response to rhGH therapy should be reevaluated. The causes can be categorized by the IGF-1 level (algorithm 1):

IGF-1 level below target range (IGF-1 <0 SD)

Poor adherence to rhGH treatment or a technical issue with its administration.

Subtherapeutic dose of rhGH.

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

Development of neutralizing antibodies to rhGH – Patients who develop neutralizing antibodies to rhGH tend to have an initial typical growth response to rhGH treatment over the first three to six months and then suddenly have a diminution of their growth rate, with low levels of IGF-1 despite adequate dosing of rhGH, 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 [MIM #262400]) [30,31]. 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-1 (mecasermin). (See "Growth hormone insensitivity syndromes".)

IGF-1 level usually below target range – Growth failure due to the following causes are usually associated with IGF-1 levels below the target range (ie, below the normal range or in the lower one-half of the normal range [IGF-1 <0 SD]), but IGF-1 levels may vary depending on the patient's nutritional status:

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). (See 'Laboratory monitoring' below.)

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

IGF-1 level within or above the target range (IGF-1 >0 SD)

Incorrect diagnosis of GH deficiency. (See "Diagnostic approach to children and adolescents with short stature".)

IGF-1 receptor mutations; these are very rare. (See "Growth hormone insensitivity syndromes", section on 'IGF-1 resistance'.)

Laboratory monitoring — For children who achieve IGF-1 levels in the target range after initial dose adjustments, we continue rhGH therapy and measure IGF-1 levels every 6 to 12 months.

For patients with multiple pituitary hormone deficiencies, adrenal and thyroid function should be reassessed a few months after initiation of rhGH therapy and periodically by measuring 8 to 9 AM serum cortisol and free T4, respectively [22]. Free T4 should be measured because this type of hypothyroidism is usually central and would not be detectable with thyroid-stimulating hormone (TSH) screening alone.

Dosing during puberty — If a prepubertal patient initially responds well to rhGH treatment but then fails to achieve the expected height velocity of the pubertal growth spurt, a temporary increase in rhGH dose (eg, to 70 to 100 micrograms/kg/day) has been suggested [32]. However, the 2016 GH consensus guidelines recommend against the routine use of this dosing paradigm because the safety and efficacy are not established [22].

The main evidence behind this strategy comes from a single randomized trial of 48 children with GH deficiency who were treated with either standard-dose rhGH (43 micrograms/kg/day) or high-dose rhGH (70 micrograms/kg/day) during puberty [33]. By the end of the pubertal growth spurt, children treated with high-dose rhGH were approximately 3.6 cm taller than those treated with standard-dose rhGH. The high dose of rhGH was, in some cases, associated with marked elevations in serum IGF-1 levels and/or symptoms consistent with GH excess (ankle swelling or hip pain). Hence, great care must be employed when using such high doses of rhGH. Of note, these findings may not be relevant to children whose dose of rhGH is periodically readjusted during rhGH therapy based on serum IGF-1 levels, as we suggest above.

Thus, the modest gains in height achieved by giving higher doses of rhGH during puberty must be balanced against the concerns for adverse effects, which are not well studied, as well as the substantial cost of the additional rhGH. In general, effective treatment with rhGH prior to puberty is more efficacious and cost-effective than efforts to accelerate growth during puberty. (See 'Growth' below.)

For children with inadequate pubertal growth due to late initiation of rhGH therapy, adjunctive treatment with a gonadotropin-releasing hormone (GnRH) agonist or aromatase inhibitor (in boys) has been explored. However, these treatments are not generally recommended, nor have they been rigorously evaluated and shown to be effective and safe. (See 'Adjunctive growth-promoting agents' below.)

OUTCOMES OF GROWTH HORMONE THERAPY

Growth — Adult height data are available in multiple studies of recombinant human growth hormone (rhGH) treatment for pediatric GH deficiency. Analysis of these data has shown that certain baseline variables predict greater total height increments and outcomes. As examples, among 1258 patients with GH deficiency from the Pfizer International Growth Study (KIGS), the variables with highest positive correlation were the midparental height standard deviation (SD) and the first-year height velocity [29]. Analysis of 2165 patients with GH deficiency from the French population-based registry showed factors that predicted a more robust response to rhGH therapy were younger age at start of rhGH treatment, greater bone age delay at initiation of therapy, and more severe GH deficiency [34].

Bone mass — Children with GH deficiency have low bone mass compared with age- and size-matched control children. Bone mass increases during rhGH treatment, and this may be considered an additional goal of therapy. To maximize peak bone mass, it is important to consider the continuation of rhGH treatment, even after linear growth has ceased, until full skeletal (and body composition) maturation has occurred and possibly beyond [35]. (See 'Duration of therapy' below and "Growth hormone treatment during the transition period", section on 'Decision to treat in individuals who remain GH-deficient as adults'.)

The effect of rhGH treatment on bone mass was illustrated by a study of children with GH deficiency who had an increase of more than 1.5 SD in bone density Z-score during five years of rhGH therapy [36]. These findings suggest that rhGH therapy increases bone mass and the progression toward peak bone mass [37]. Without adequate rhGH replacement, either childhood- or adult-onset GH deficiency can be associated with low bone mass during adulthood [38,39]. (See "Growth hormone deficiency in adults", section on 'Bone mineral density and fractures'.)

ADVERSE EFFECTS OF GROWTH HORMONE THERAPY — Treatment of children with recombinant human growth hormone (rhGH) has generally been safe [40-42].

Acute effects — Among children treated with rhGH, the most common treatment-associated complaint is headaches, which usually are benign. In addition, there appears to be a slightly higher risk of developing idiopathic intracranial hypertension (formerly known as pseudotumor cerebri), increased intraocular pressure [43], slipped capital femoral epiphysis [44], and worsening of existing scoliosis [40]. Whether these are true side effects of rhGH itself or whether some are related to the rapid growth induced by rhGH remains unknown. Nonetheless, patients should be routinely monitored for these issues during GH therapy.

Intracranial hypertension generally occurs shortly after treatment initiation or dose increases and usually resolves with discontinuation of rhGH therapy. Treatment can often be resumed at a lower dose without return of symptoms, with slower escalation back up to standard doses. Slipped capital femoral epiphysis also occurs soon after rhGH therapy is initiated, and 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. (See "Idiopathic intracranial hypertension (pseudotumor cerebri): Epidemiology and pathogenesis" and "Evaluation and management of slipped capital femoral epiphysis (SCFE)".)

Other rare adverse effects are severe hypersensitivity reactions, pancreatitis, transient gynecomastia, and an increase in the growth and pigmentation of nevi, without malignant degeneration (table 1) [40,45]. Carpal tunnel syndrome, edema, and arthralgia are more common in adults undergoing rhGH 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 [46]. Rarely, a child treated with rhGH develops neutralizing antibodies, resulting in loss of efficacy [47,48].

Development of insulin resistance and disorders of glucose intolerance may occur in children receiving rhGH 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 rhGH identified 18 new cases of type 2 diabetes mellitus and 14 of impaired glucose tolerance [49]. 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 rhGH therapy.

Long-term risks

Cancer and mortality – Concerns have been raised about a possible role for rhGH or its mediator insulin-like growth factor 1 (IGF-1) in cancer risk; these concerns are primarily based on observations that higher IGF-1 levels in normal individuals are associated with increased risks for breast or prostate cancer [50].

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

Isolated growth failure – For patients with isolated growth failure (isolated GH deficiency, idiopathic short stature, or born small for gestational age [SGA]/prenatal growth failure) and no other risk factors, rhGH 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 rhGH treatments in Europe (SAGhE) study, which followed almost 24,000 patients, approximately one-half of whom had isolated growth failure [51]. In long-term follow-up, the patients with isolated growth failure had no overall increase in cancer risk (standardized incidence ratio 1.0, 95% CI 0.6-1.4) or cancer mortality compared with the general population. The certainty about this conclusion is somewhat limited because of the rarity of cancer in this cohort (23 cases among 11,062 treated subjects), limited length of follow-up (mean 14.8 years per patient), and lack of untreated control groups with the same causes for growth failure. A lack of association with cancer was also found in prior studies with shorter length of follow-up [52-56], including some that focused primarily on leukemia [57-59]. In a subsequent report on the same cohort, cancer-related mortality was not increased for those with isolated GH deficiency or idiopathic short stature (standardized mortality ratio [SMR] 0.9, 95% CI 0.4-1.8; mean follow-up 16.3 years) or SGA subjects (SMR 0.6, 95% CI 0.1-2.4; mean follow-up 17.2 years) [60]. SGA subjects exhibited some excess total mortality related to diseases of the circulatory system (SMR 3.7, 95% CI 1.7-8.3) that was not related to rhGH dose and is consistent with established risks for the underlying diagnosis.

Primary cancer diagnosis – Patients with a primary cancer diagnosis or underlying conditions associated with cancer risk (hematopoietic stem cell transplantation, Down syndrome, Langerhans cell histiocytosis) experienced a substantial increase in overall mortality (SMR 17.1, 95% CI 15.6-18.7) and cancer-related mortality (SMR 117.3, 95% CI 105.4-130.6; mean follow-up 15.4 years) compared with expected risks for the general population [60]. This excess cancer-related mortality was not associated with daily or cumulative rhGH dose. 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 was probably not related to the rhGH treatment.

Further information about secondary cancers is provided by a report from a cohort of 2582 survivors of childhood solid-organ cancers, of whom 374 (14 percent) developed secondary cancers, including 40 who had received rhGH therapy [61]. In multivariate analysis that adjusted for the type of primary cancer and cranial radiation dose, rhGH therapy was not associated with an increased risk of developing a second tumor (relative risk 1.3, 95% CI 0.9-2.0). There was a nonsignificant increase in the risk of meningioma, which has also been suggested by other studies [62-64]. If this is a true association, it could be due to cranial irradiation and/or undetermined meningioma-predisposing conditions and not to rhGH treatment itself. This long-term outcome study supports the overall safety of rhGH therapy even in a population at relatively high risk for recurrence or secondary neoplasm but also underscores the importance of the need for lifelong follow-up for secondary neoplasms regardless of the history of rhGH therapy.

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 rhGH therapy [22]. Others question the need for this waiting period for craniopharyngiomas.

Other noncancer primary diagnoses – For patients with other noncancer primary diagnoses, there was a modest increase in overall mortality (SMR 3.8, 95% CI 3.3-4.4) and cancer-related mortality (SMR 2.4, 95% CI 1.4-4.1) [60]. This cohort included subjects with multiple pituitary hormone deficiencies, several syndromes with known mortality risks (Turner, Noonan, and Prader-Willi syndromes and neurofibromatosis type 1), and severe congenital malformations. This increased mortality is unlikely to be related to the rhGH treatment because the SMR was not related to daily or cumulative rhGH dose and because these patients have underlying diagnoses associated with increased mortality.

Stroke – A separate study from the French SAGhE group raised concerns for an increased risk of hemorrhagic stroke in adults who were treated with rhGH in childhood [65]. However, subsequent expert review of this study from the Endocrine Society (ES), Pediatric Endocrine Society (PES), and GH Research Society (GRS) suggests important deficiencies in the study methods that warrant skepticism about its conclusions [66]. This study does not provide sufficient evidence to change prescribing practices or warrant increased surveillance for stroke in adults who were treated with rhGH during childhood [66].

Prior to 1985, GH was derived from pituitary glands of deceased humans. This preparation transmitted Creutzfeldt-Jakob disease to a few children [67]. There is no risk for this disease with the rhGH preparations that are used in the modern era.

DURATION OF THERAPY — Recombinant human growth hormone (rhGH) therapy is generally continued at least until linear growth decreases to less than 2.0 to 2.5 cm (0.8 to 1 inch)/year [22]; however, this is an individualized decision and, in some adolescents, it may be appropriate to terminate therapy sooner. Patients should then be retested for GH deficiency using a rhGH stimulation test to determine if treatment should be continued into adulthood for metabolic indications, ie, to maintain healthy body composition, lipid profiles, and bone mass.

Among children with isolated GH deficiency, more than two-thirds will have normal results when retested for GH deficiency as adults. Because the majority of these patients with isolated GH deficiency during childhood will be GH-sufficient as adults, it is important to repeat the GH stimulation test during the transition period to determine if they will require ongoing therapy. By contrast, 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, and intracranial irradiation, or associated with multiple pituitary hormone deficiencies).

The indications, timing, and technique for retesting for GH deficiency during the transition period are discussed in detail separately. (See "Growth hormone treatment during the transition period".)

ADJUNCTIVE GROWTH-PROMOTING AGENTS — In patients in whom recombinant human growth hormone (rhGH) treatment is not begun until adolescence, the child may not achieve desired adult height with rhGH therapy alone, because there already may be significant partial closure of the growth plates. To delay further epiphyseal maturation, adjunctive treatment with a gonadotropin-releasing hormone (GnRH) agonist or an aromatase inhibitor has been explored. However, these treatments are not generally recommended for this population, because the efficacy and safety have not been established, as outlined below:

GnRH agonist – We do not generally recommend adjunctive treatment with a GnRH agonist with rhGH therapy, because of limited evidence for benefit and some safety concerns. For male and female adolescents with GH deficiency who start treatment in early to mid-puberty, a few studies suggest that the addition of a GnRH agonist to rhGH treatment may result in a taller near-adult height [68-70]. However, the use of this approach in children with GH deficiency remains controversial: Although GnRH agonists can theoretically increase adult height by delaying epiphyseal closure, thereby allowing more time for growth during puberty, long-term treatment (>3 years) is likely required to accomplish this goal. Furthermore, it has not been established that GnRH agonist treatment yields greater increases in height compared with rhGH treatment alone if rhGH treatment is initiated prior to puberty. In addition, the clinician must consider multiple issues when considering addition of GnRH agonist therapy, including risks of potential reduced bone mineralization, psychological effects of halting puberty, and cost-benefit analysis [71,72]. Instead, it is preferable to make a timely diagnosis of GH deficiency and initiate rhGH therapy prior to puberty; this usually provides sufficient height gains such that GnRH agonist therapy is not necessary.

Aromatase inhibitors – We do not generally recommend adjunctive treatment with aromatase inhibitors (letrozole and anastrozole) with rhGH therapy for adolescent males. The rationale for this approach is that aromatase inhibitors might augment growth potential by decreasing estrogen synthesis, thus delaying epiphyseal fusion. As a byproduct, testosterone levels are reciprocally elevated to varying degrees. However, this approach should be considered experimental because clinical data on outcomes are limited [73,74]. A systematic review concluded that aromatase inhibitors increase short-term growth rates in male children with GH deficiency but that there is no evidence to suggest that they increase adult height [75].

Aromatase inhibitor therapy should not be administered to girls, because this approach would be expected to diminish estrogen production and potentially raise testosterone levels.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Growth hormone deficiency and other growth disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: My child is short (The Basics)")

SUMMARY AND RECOMMENDATIONS

Physiologic actions of growth hormone (GH) – GH promotes linear growth in children by stimulating cartilage growth, particularly at the epiphyseal plate. In addition, GH increases lean body mass and bone mass and reduces fat mass, while increasing liver lipid content. Physiologic concentrations of GH generally have a beneficial effect on the plasma lipid profile, although either GH deficiency or excess may be associated with dyslipidemia. (See 'Physiologic actions of growth hormone' above.)

Diagnosis of GH deficiency – If GH deficiency is congenital and complete, the diagnosis is relatively easy to confirm. Affected children present with severe growth failure and very low serum concentrations of GH, insulin-like growth factor 1 (IGF-1), and insulin-like growth factor-binding protein 3 (IGFBP-3), the major binding protein of circulating IGF-1. Infants with GH deficiency may also manifest hypoglycemia, prolonged jaundice, microphallus (in males), and giant-cell hepatitis. In those diagnosed later, delayed bone age is characteristic. (See 'Diagnosis of growth hormone deficiency' above and "Diagnosis of growth hormone deficiency in children".)

Treatment with recombinant GH

Indications and dosing – For children diagnosed with GH deficiency whose epiphyses are open, we recommend treating with recombinant human growth hormone (rhGH) rather than no treatment (Grade 1B). The typical range of starting doses of rhGH is between 20 and 35 micrograms/kg/day, given subcutaneously once daily (0.16 to 0.24 mg/kg/week), with the lower end of the range used for patients with severe GH deficiency. Treatment should be started at the youngest possible age to achieve the greatest growth response. Longer-acting rhGH formulations designed for once-weekly dosing, including lonapegsomatropin and somapacitan, are now available. (See 'Formulations of growth hormone' above and 'Growth hormone treatment' above.)

Monitoring and dose adjustment – We suggest measuring IGF-1 approximately five weeks after beginning daily rhGH treatment or making a dose adjustment, and lowering the rhGH dose if the level is above the normal range (Grade 2C). If a long-acting rhGH preparation is used (lonapegsomatropin, somapacitan, or somatrogon), interpretation of the IGF-1 result depends on the timing of the sample compared with the preceding dose. It is also a reasonable practice to use IGF-1 results to "fine-tune" rhGH doses (algorithm 1). This is based upon limited evidence suggesting that IGF-1-based dosing may increase short-term height velocity and is sometimes dose-sparing, although adult height outcomes using this approach are lacking. (See 'Dose adjustment based on IGF-1 response' above.)

Height velocity is monitored at three- to six-month intervals (algorithm 1); the goal for treatment is to attain the 75th percentile for height velocity for age during catch-up growth. We also monitor IGF-1 levels every 6 to 12 months. (See 'Ongoing monitoring' above.)

Outcomes – The growth response to rhGH is highly variable. Predictors of a greater height response to rhGH treatment include younger age and greater deviation of actual height from target height (genetic potential) at the start of therapy. In addition, a more frequent dosing schedule (for aqueous formulations of rhGH) and higher dose of rhGH tend to correlate with increased height, but this relationship is not linear. (See 'Growth' above.)

Duration of therapy – We recommend continuing rhGH therapy at least until linear growth is nearly complete (eg, height velocity less than 2.0 to 2.5 cm/year) (Grade 1B). Patients should then be retested for GH deficiency to determine if treatment should be continued into adulthood. The majority of individuals diagnosed with isolated GH deficiency in childhood have normal GH secretion during adulthood, presumably because of the stimulatory effects of gonadal steroid hormones on GH secretion. By contrast, children with genetic and organic forms of GH deficiency, multiple pituitary hormone deficiencies, and/or structural abnormalities of the hypothalamic-pituitary region rarely become GH-sufficient. (See 'Duration of therapy' above and "Growth hormone treatment during the transition period".)

Adjunctive therapy – For children who are not likely to achieve an adequate height response to rhGH because their growth plates are nearing closure, adjunctive therapy to delay epiphyseal maturation may be considered, but the efficacy and safety of these approaches are not well established. (See 'Adjunctive growth-promoting agents' above.)

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Topic 5843 Version 40.0

References

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