Growth hormone treatment for idiopathic short stature

INTRODUCTION — Treatment of children and adolescents with recombinant human growth hormone (rhGH) for idiopathic short stature (ISS) is controversial for two reasons. First, the response to rhGH is highly variable, probably because of the heterogeneous endocrinologic profile in children with ISS, and those children who respond to rhGH treatment may have only modest increases in linear growth. Second, there is little evidence that short stature represents a substantial psychosocial burden to most short children. The possible psychosocial benefit must be weighed against the substantial cost and possible adverse effects of treatment.

The efficacy and potential risks of rhGH and alternative treatments for children with ISS are discussed below. The clinical evaluation of children with short stature is discussed separately. (See "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)

CLINICAL FEATURES

Definition — Idiopathic short stature (ISS) is a clinical description rather than a disease. A practical definition of ISS is a height below 2 standard deviations (SD) of the mean for age (ie, below the 2.3^rd percentile), in the absence of any endocrine, metabolic, or other disease that explains the short stature [1,2]. In defining ISS for the indication of recombinant human growth hormone (rhGH) treatment, the US Food and Drug Administration uses the more stringent criterion of 2.25 SD below the mean (ie, the 1.2^nd percentile) and a predicted adult height that is below the normal range; this corresponds to an adult height <63 inches (160 cm) for males and <59 inches (150 cm) for females in the United States. The clinical approach to diagnosis of ISS is discussed separately. (See "Diagnostic approach to children and adolescents with short stature".)

ISS is generally considered a variant of normal growth (since pathologic causes are excluded by definition). However, some children formerly considered to have ISS, especially those with familial short stature with one parent significantly shorter than the other, may be heterozygous for some gene variants that affect growth plate development, eg, NPR2 [3] (see "Causes of short stature", section on 'Skeletal dysplasias/growth plate abnormalities'). Other normal variants are familial short stature and constitutional delay of growth and puberty (CDGP), sometimes called constitutional short stature for prepubertal children. There is ongoing controversy about the nomenclature of ISS. We use the term to refer to nonfamilial cases, but some other experts consider familial short stature and CDGP to be subcategories of ISS [1,4]. In either case, it is clear that there is considerable overlap among these variants, and many healthy children with short stature have growth characteristics consistent with more than one of these categories. The term ISS is generally reserved for children at the more severe end of the spectrum in each category, but the distinction between normal and abnormal growth patterns is not clear. (See "Causes of short stature", section on 'Normal variants of growth'.)

Endocrine findings — Children with ISS often have normal height velocity (often near or at the lower limit of normal), no biochemical or other evidence for a specific growth-restricting condition, and normal results on GH stimulation tests. Thus, children with ISS do not have GH deficiency according to the classic criteria.

Nonetheless, some children with ISS have relatively low serum concentrations of insulin-like growth factor 1 (IGF-1) and normal or elevated serum GH levels, suggesting that they may be relatively insensitive to the effects of GH [5,6]. These children may respond to supraphysiologic levels of GH given as treatment or induced by stimulation by IGF-1. However, a reduced level of IGF-1, in combination with a normal or minimally elevated GH level, is much more often the result of chronic illness or undernutrition, which is often concomitantly present in a short child. IGF-1 results should be interpreted in the context of the child's age because levels normally increase with age, especially during puberty. These caveats should be considered when interpreting the endocrine findings of a child with short stature. (See 'Other treatments' below and "Diagnosis of growth hormone deficiency in children", section on 'IGF-1 and IGFBP-3'.)

Exclusion of other diagnoses — Many systemic diseases and conditions may contribute to short stature, including renal, neoplastic, pulmonary, cardiac, gastrointestinal, immunologic, and metabolic disease. In addition, some therapies such as corticosteroid treatment can cause growth failure. Presence of significant disease in these categories precludes the diagnosis ISS.

The evaluation of a child for short stature always begins with analysis of height velocity using serial measurements of height, interpretation of the child's growth trajectory in the context of parental heights, and, in most cases, radiographic determination of bone age to permit an estimate of adult height and to evaluate for growth potential. Even without a bone age determination, a reasonably accurate near-adult height prediction may be made [7]. However, even with bone age determination, adult height predictions have only moderate accuracy and a wide 95 percent confidence interval. Due to the possibility of skeletal dysplasia in children with presumed ISS, careful attention should be paid to body proportions (limbs disproportionately short for the trunk or vice versa) and the bony structures from the hand-wrist radiograph.

In otherwise healthy children, the yield of additional laboratory testing is extremely low [8,9]. There is some controversy about the extent of testing that should be performed for children and adolescents with presumed ISS. Because of the low diagnostic yield and high cost, we suggest performing laboratory testing only selectively in otherwise asymptomatic children, as outlined in a separate topic review. (See "Diagnostic approach to children and adolescents with short stature", section on 'Features suggesting genetic or endocrine disease'.)

Psychosocial functioning — Most patients with ISS have normal psychosocial functioning. It is likely that there is substantial variation in the psychological effects of short stature and that shortness has adverse effects on some individuals but not others. This is supported by a systematic review, which concluded that children and adults with short stature may experience a small diminution in quality of life [10].

In most children with extremes of short or tall stature, there is minimal impact on peer perceptions of social behavior, friendship, or peer acceptance [11]. As an example, in a population-based sample, a few short children had problems with peer relationships, but short stature could not be established as the cause of the disturbance. Some negative stereotypes regarding the social adjustment of individuals were noted (eg, teasing and bullying, less social acceptance, and fewer friends) [12]. The psychosocial effects of severe short stature (height <-2.5 SD) have not been adequately studied [1].

Clinic-based populations may display greater psychosocial dysfunction, likely because children referred for medical treatment for their short stature are selected for a higher level of parental (or child) concern. Children referred for treatment may have significantly more externalizing behavior problems and poorer social skills [13]. However, in this population, more problems were identified by the parents' report and children tended to score normally on measures of self-esteem and functioning when based on the child's self-report or report of teachers [14].

GROWTH HORMONE THERAPY — Therapy with recombinant human growth hormone (rhGH) for children with ISS is approved by the US Food and Drug Administration. The indication is for children with current height below -2.25 standard deviations (SD) of the mean, in whom the epiphyses are not closed and whose expected adult height (based on bone age) is below the normal range; this corresponds to an adult height less than 63 inches (160 cm) for males and 59 inches (150 cm) for females in the United States [15]. rhGH is not approved for treatment of ISS in many other countries, including the European Union. (See "Diagnostic approach to children and adolescents with short stature", section on 'Prediction of adult height'.)

rhGH therapy should ideally be initiated in early childhood, for optimal efficacy [1]. (See 'Efficacy' below.)

Decision to treat — Despite US Food and Drug Administration approval, the use of rhGH for children and adolescents with ISS remains controversial. Guidelines recommend against the routine use of rhGH for every child with ISS [16]. Instead, the decision about whether to administer rhGH should be made on a case-by-case basis after a detailed discussion with the child and family. This is because there are several limitations and uncertainties about the use of rhGH therapy for children with ISS. Understanding these limitations informs a pragmatic and personalized approach to selecting patients for rhGH therapy.

●Limitations and uncertainties:

•There is little evidence that short stature has a consistent detrimental effect on an individual's psychosocial or physical functioning. (See 'Psychosocial considerations' below.)

•The available evidence suggests only modest efficacy for rhGH treatment in children and adolescents with ISS, which must be weighed against the potential adverse physiologic, psychosocial, and/or financial effects of the treatment. (See 'Safety' below and 'Psychosocial considerations' below and 'Costs' below.)

•There is substantial interindividual variability in responsiveness to rhGH among children with ISS, and some children probably do not respond to treatment [16]. Moreover, it is difficult to predict responsiveness to rhGH treatment for the typical short child due to the clinical and molecular heterogeneity of the condition, inconsistent criteria used for the definition of ISS, and variable rhGH treatment doses used in clinical trials [17-21]. Clinical trials tend to enroll children with more severe short stature, so the reported growth response may not be generalizable to the less severe short stature seen in a clinical population. (See 'Efficacy' below.)

●Practical solutions – These uncertainties yield the following practical approaches to decisions about rhGH therapy:

•The evaluation should attempt to identify children with growth patterns consistent with constitutional delay of growth and puberty (CDGP) because they are likely to have catch-up growth without rhGH treatment. Clinical evidence supporting CDGP includes delayed bone age and/or history of delayed growth and puberty in a parent (table 1). Moreover, adolescent boys with CDGP and moderate short stature (taller than -2.5 SD) are more appropriately treated with testosterone replacement rather than rhGH. (See "Diagnostic approach to children and adolescents with short stature" and 'Testosterone' below.)

•The family should be aware that short stature does not generally have a detrimental effect on psychosocial functioning. At the same time, efforts should be made to determine if this is likely to be the case for the individual patient. (See 'Psychosocial considerations' below.)

•It is essential to establish realistic expectations about the likely growth outcome of rhGH therapy. (See 'Expectations' below.)

•If rhGH therapy is undertaken for children or adolescents with ISS, growth should be reevaluated after a treatment trial and therapy continued only for those who exhibit accelerated growth. (See 'Our approach' below.)

The decision to treat should be made collaboratively with the family and patient after a full discussion of each of these issues [16]. The psychosocial considerations should be emphasized because they depend on individual patient characteristics and are often misunderstood, as detailed in the following section.

Psychosocial considerations — The decision to treat children and adolescents with ISS using rhGH requires complex psychosocial considerations [11,22]. The treatment should be considered only if the short stature represents a disability to the child and is not amenable to counseling and reassurance and if growth augmentation is likely to provide psychosocial benefit to the child. If rhGH therapy achieves an increase in height, it might be expected to improve a child's self-image and social efficacy. On the other hand, some have speculated that rhGH therapy could have adverse psychosocial consequences because it draws the child's attention to their short stature [22,23], in addition to the treatment burden from daily subcutaneous injections. A meaningful benefit/cost assessment must be applied [24].

Treatment with rhGH appears to have little or no effect on psychosocial outcomes, according to the few small studies that have addressed this issue. (See 'Psychosocial outcomes' below.)

Expectations — When considering rhGH therapy, it is essential to establish realistic expectations since unmet expectations can have adverse effects. Children presenting for rhGH therapy and their parents/caregivers often believe that the treatment will make them of average height or taller than average. However, even if the treatment is successful, most patients will still be short as adults. As an example, if a boy's predicted adult height is 155 cm (61 inches) and rhGH therapy is successful in adding 5 cm (2 inches), which is a typical expected increase [25], their adult height will still only be 160 cm (63 inches).

A study of parents seeking subspecialist care for their child's short stature showed that most parents have high expectations that their child's quality of life will improve with rhGH treatment; these expectations are unlikely to be met [26].

Costs — Treatment costs of rhGH therapy are substantial and present an important consideration for allocation of medical resources. The costs and coverage of rhGH treatment by insurance companies vary significantly from country to country. The insurance industry has instituted progressive restrictions on coverage for rhGH in children/adolescents with ISS [27].

Efficacy

Height outcomes — Assessment of the published clinical trials of rhGH treatment in children and adolescents with ISS is complicated by the use of variable inclusion criteria, rhGH doses, and outcomes; small sample sizes; high dropout rates (usually skewed to those with the least response); and lack of an adequate control group (in most studies). The studies generally support the conclusion that rhGH treatment results in modest increases in short-term growth rates and in adult height, although treated individuals remain relatively short compared with their peers. Studies of rhGH treatment using typical protocols for children with ISS report mean increases in adult height ranging from 4 to 10 cm (approximately 0.67 to 1.67 SD), compared with predicted adult height (table 2) [18-20,25,28,29]. However, there is wide interindividual variation in height outcomes, including no increase in adult height for some children [16]. Height velocity and adult height outcomes are generally greater when rhGH is initiated during early childhood; a consensus conference concluded that the optimal age for initiating rhGH therapy is between age five years and early puberty [1].

Patient characteristics that predict a greater response to rhGH treatment for children with ISS include [1,17,21,30-33]:

●Height at start of treatment (the taller the better)

●Age at start of treatment (the younger the better, if after age five)

●Height response during the first year of rhGH treatment (the greater the initial response, the better the long-term outcome)

●Midparental height (the taller the parents, the better)

In addition, higher doses of rhGH generally are associated with a greater response [34-36]; this observation has led to individualized approaches to dosing, as discussed below. (See 'Dosing' below.)

Psychosocial outcomes — Effects of rhGH treatment on psychosocial functioning were addressed in three small studies with untreated controls [37-39]. None showed differences between the treatment groups in behavior, self-esteem, or quality of life. However, these studies were limited by small sample size (approximately 30 children in each study).

Specific effects of rhGH treatment on child behavior and social functioning were addressed in a placebo-controlled trial of 68 children with ISS [40]. In this study, there was a significant decrease in behavioral problems among the group treated with rhGH when compared with placebo, as measured by parent report, but both groups remained in the normal range for these measures. There were no differences in measures of social competency. The study was limited by small sample size and male predominance. Because it compared rhGH treatment to placebo, this study did not address the nonspecific effects of rhGH treatment (for example, whether the focus on a child's stature conferred by treatment might have adverse psychosocial consequences).

Safety — Therapy with rhGH at standard doses appears to have minimal physiologic adverse effects. Safety studies have examined a variety of possible adverse effects, including idiopathic intracranial hypertension (pseudotumor cerebri), increased intraocular pressure, reduced insulin sensitivity, slipped capital femoral epiphysis, worsening of existing scoliosis, and possibly of pancreatitis. Placebo-controlled trials have generally shown no increase in these or other adverse effects as compared with placebo [17,19], but these studies are not adequately powered to detect rare adverse events, have limited length of follow-up, and use a variety of dosing schemes. Data from large postmarketing surveillance studies suggest that these risks are minimal with the rhGH doses that are typically used for therapy [21,41]. High-dose rhGH treatment (71 mcg/kg/day) was reported to accelerate the onset of puberty and epiphyseal closure in children with ISS [42], but lower doses (34 or 53 mcg/kg/day) did not [43]. Overall, the physiologic adverse effects of rhGH for patients with ISS are similar to or less than those seen in children treated for GH deficiency or Turner syndrome [44,45]. The possibility of an increased risk for cancer has been raised and examined closely in long-term studies. Data suggest that each of these risks is very low with the rhGH doses that are typically used. (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)

Excessive rhGH doses might be associated with more significant adverse effects, as suggested by the complications found in patients with substantial GH excess, such as those with acromegaly. These include edema, cardiomyopathy, insulin resistance, stroke, increased intraocular pressure, arthropathy, idiopathic intracranial hypertension, and gynecomastia. Some, but not all, studies of adults with acromegaly have suggested an increased incidence of colonic and uterine neoplasia. The risks of giving excessive doses of rhGH may theoretically be reduced by using insulin-like growth factor 1 (IGF-1)-targeted dosing strategies. (See 'Dosing' below.)

Dosing

Starting dose — We suggest initiating rhGH at a dose of approximately 0.24 to 0.3 mg/kg/week (35 to 43 mcg/kg/day), given once daily by subcutaneous injection [16]. Sustained-release formulations (for weekly dosing) are available but not approved for ISS. The optimal dosing range for children with ISS is not well established. In prepubertal children with ISS, rhGH routinely is used in the range of 0.3 to 0.47 mg/kg/week (43 to 67 mcg/kg/day). Some clinicians, including the authors of this topic review, readjust the dose based on growth response and/or IGF-1 levels. (See 'Dose adjustment for IGF-1 levels' below.)

Higher doses lead to modest increases in short-term height velocity and predicted adult height [34]. In a multicenter study of children with ISS, rhGH doses of 0.37 mg/kg/week (53 mcg/kg/day) were significantly more effective than doses of 0.24 mg/kg/week (35 mcg/kg/day) [35]. Adult height was increased by 7.2 and 5.4 cm (from predicted adult height at entry), respectively, in the two treatment groups, and 94 versus 71 percent were within the range of normal adult height (within 2 SD of the mean).

These rhGH doses are substantially higher than those used for children with GH deficiency, which are commonly in the range of 20 to 40 mcg/kg/day. This reflects the relatively lower sensitivity to GH in children with ISS. (See "Treatment of growth hormone deficiency in children".)

Dose adjustment for IGF-1 levels — We suggest adjusting rhGH dosing based on insulin-like growth factor 1 (IGF-1) levels when treating children with ISS, targeting an IGF-1 level at approximately 1 SD above the mean for age and sex. We choose this target based on general considerations of cost-effectiveness and to avoid theoretical safety concerns that may be associated with excessive rhGH dosing. If IGF-1 levels are consistently elevated (>2.5 SD), we reduce the rhGH dose [1]. We check IGF-1 levels approximately four weeks after beginning therapy or changing the rhGH dose and approximately every 6 to 12 months thereafter, similar to the approach we use for patients with GH deficiency. Optimization and cost-effectiveness of this technique require further study [46,47]. (See "Treatment of growth hormone deficiency in children", section on 'Dose adjustment based on IGF-1 response'.)

IGF-1-targeted dosing is an established approach for treating children with GH deficiency, in whom it appears to improve efficacy and may also avoid potential risks of excessive rhGH doses [1]. The utility of this approach for children with ISS is inferential and based on preliminary data. The rationale is that children with ISS may have a variety of abnormalities in the GH-IGF-1 axis, conferring varied levels of GH sensitivity. Some studies in children with GH deficiency or ISS suggest GH responsiveness is closely associated with IGF-1 levels during treatment [17,48]. In addition, some side effects of rhGH, such as arthralgia and edema, are associated with supraphysiologic IGF-1 levels in other populations. (See 'Safety' above.)

For patients with ISS and significant GH resistance (ie, those with very low IGF-1 levels, sometimes referred to as "partial GH insensitivity" or "partial IGF-1 deficiency"), the optimal approach to treatment is unclear. Some of these children may require higher rhGH doses to achieve a growth response, whereas others seem to respond particularly well to standard doses of rhGH [46,49,50]. Moreover, this is also the group for which direct replacement of IGF-1 may be most effective. Clinical trials will be necessary to determine the roles of rhGH versus recombinant IGF-1, or rhGH combined with recombinant IGF-1, in subsets of children with ISS. (See 'Recombinant human IGF-1' below.)

Our approach — We use a starting dose of rhGH of 0.24 to 0.3 mg/kg/week (35 to 43 mcg/kg/day) for children with ISS, given by daily subcutaneous injection. We then adjust the dose based on serial measures of IGF-1, titrating up or down as needed, with the goal of keeping the IGF-1 level at approximately 1 SD above the mean for age and sex (see 'Dose adjustment for IGF-1 levels' above). This is similar to our approach to rhGH dosing for children with GH deficiency.

Because the response to treatment is variable, the height velocity and treatment plan should be reevaluated periodically.

●After one year of therapy, we decide whether to continue treatment based on the growth response [16]:

•If a patient has had a good response to rhGH treatment, we continue treatment. We define a good response as an increase in height velocity of 50 percent or at least 2.5 cm/year above the baseline height velocity.

•If a patient has a poor response to rhGH despite adherence to treatment and appropriate dosing according to IGF-1 levels, then rhGH treatment should be stopped and alternative therapies considered [1]. (See 'Other treatments' below.)

●If the initial growth response is good (at least 2.5 cm/year above the baseline height velocity after one year of treatment), we continue treatment until linear growth decreases to less than 2.0 to 2.5 cm (approximately 1 inch)/year. This usually occurs in late puberty, equating to a bone age of 13 to 13.5 years in girls or 15.5 to 16 years in boys.

●A particularly low IGF-1 level (eg, IGF-1 level <-2 SD, especially if using bone age-matched normative data) in an apparently healthy patient with ISS may indicate "partial GH insensitivity" (also known as "partial IGF-1 deficiency"), provided that inadequate nutrition and subclinical systemic illness have been excluded. In this setting, it is reasonable to proceed with a trial of rhGH therapy, recognizing that responsiveness to rhGH is highly variable in this group of patients. If the patient's growth does not accelerate significantly during the treatment trial, then we do not continue treatment, provided that treatment adherence is confirmed. In this case, treatment with recombinant IGF-1 might be considered. (See 'Recombinant human IGF-1' below.)

OTHER TREATMENTS — As the molecular basis for short stature becomes better characterized, especially for genes functioning at the growth plate [3], treatments other than recombinant human growth hormone (rhGH) or combined with rhGH may emerge as alternatives or advances over current practice for some subgroups. At present, the following treatment alternatives might be helpful for some subgroups of children with ISS, but there is insufficient evidence to determine selection criteria or efficacy in this population.

Testosterone — Treatment with testosterone is an option for boys with features of constitutional delay of growth and puberty (CDGP), ie, mild to moderate short stature and delayed puberty and bone age but with predicted adult height in the normal range for the family. In this population, testosterone treatment promotes puberty and accelerates linear growth and, if given at modest doses for short durations, does not affect adult height (either positively or negatively) [1]. Candidates for testosterone treatment typically have entered the early stages of puberty (some testicular enlargement) by age 13 or 14 years, and testosterone treatment will effectively accelerate puberty and growth. Boys who have no testicular enlargement by this age should be fully evaluated for causes of hypogonadism, including Klinefelter syndrome [51]. (See "Approach to the patient with delayed puberty", section on 'Testosterone therapy'.)

Estrogen — Similarly, in girls with pubertal delay and mild short stature, a short course of estrogen therapy can promote short-term linear growth and does not negatively affect adult height outcomes [52,53]. However, this intervention is uncommon. If it is contemplated, care should be taken to exclude other causes of pubertal delay (including Turner syndrome) and to use low doses of estrogens because estrogens promote epiphyseal closure. (See "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)

Aromatase inhibitors — Aromatase inhibitors (letrozole and anastrozole) are theorized to facilitate growth in adolescent males by delaying epiphyseal closure through inhibition of conversion of androgen to estrogen. Preliminary studies suggest that treatment of adolescent boys with aromatase inhibitors, with [54,55] or without [56,57] concomitant rhGH, may increase predicted adult height, although there may be significant variability in response related to chronologic age and bone age. In a randomized trial, combination therapy with an aromatase inhibitor and rhGH resulted in a mean near-adult height of -1.0 standard deviation (SD), compared with -1.4 SD with rhGH alone (mean height difference 1.9 cm) [55]. Only minimal short-term and no long-term safety and efficacy results are available, and thus the use of these agents for short stature is off-label and should be considered experimental [1,58,59].

Aromatase inhibitors are not candidates for treatment of short stature in girls, because they would be expected to slow growth by inhibiting estrogen production and potentially raise testosterone levels.

Gonadotropin-releasing hormone agonists — An alternative approach to attempt to increase adult height in those very short children with ISS is to delay pubertal development and epiphyseal fusion with a gonadotropin-releasing hormone agonist (GnRHa). In adolescents with normal pubertal timing, the range of the effect is limited to approximately 0 to 4 cm when the change in predicted adult height is compared with measured adult height [60]. Bone mineral density decreases during GnRHa treatment but typically normalizes after GnRHa is withdrawn. Thus, due to this low efficacy and adverse effects on bone mineral density, GnRHa therapy is not useful for treatment of short stature unless precocious puberty is present or if the adolescent is GH-deficient.

An alternative strategy is to use GnRHa therapy for one to three years in combination with standard rhGH therapy for selected patients with ISS who have a diminished height prognosis when treated with GH alone (eg, because of earlier puberty or because rhGH was not initiated before mid-puberty). In such patients, small observational studies and two small randomized trials suggest that adding GnRHa to rhGH therapy probably adds a small increment to adult height compared with predicted values [61-65]. The utility of this strategy for other rhGH-treated children with ISS has not been established. GnRHa therapy is not approved for this indication in the United States and adds significant costs to the regimen.

Recombinant human IGF-1 — Recombinant human insulin-like growth factor 1 (rhIGF-1) has been effectively used for the treatment of children with short stature due to "severe primary IGF-1 deficiency" (Laron syndrome), a rare disorder caused by complete absence or insensitivity of the GH receptor [66-68]. A preparation of rhIGF-1 (Mecasermin, Increlex) is approved by the US Food and Drug Administration for this use. (See "Growth hormone insensitivity syndromes".)

It is unclear whether rhIGF-1 has a role in the treatment of children with ISS. A subset of patients with ISS have lesser degrees of GH sensitivity and a similar endocrine profile, with normal or elevated circulating serum GH levels but low levels of IGF-1 and IGF-binding protein-3 (IGFBP-3). This condition has been termed "partial GH insensitivity" or "partial IGF-1 deficiency." Small studies suggest that patients with this type of ISS respond to treatment with rhIGF-1 [69]. However, children with this profile also appear to respond at least as well to rhGH treatment compared with those with more normal pretreatment IGF-1 levels [5,48].

Thus, there is insufficient information to determine the benefits and risks of rhIGF-1 treatment for children with ISS and whether it offers any advantage over rhGH treatment [53,70-73]. It is possible that future research will identify a subset of patients with ISS with molecular defects causing GH insensitivity, for which rhIGF-1 will be beneficial.

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 5^th to 6^th 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 10^th to 12^th 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

●Approved indications – Recombinant human growth hormone (rhGH) is approved by the US Food and Drug Administration for children with idiopathic short stature (ISS) whose current height is below -2.25 standard deviations (SD) of the mean for age, whose predicted adult height is unlikely to fall within the normal range, and whose epiphyses are not closed. The lower end of the normal range for adult height is 63 inches (160 cm) for males and 59 inches (150 cm) for females. (See 'Growth hormone therapy' above.)

●Controversies and considerations – There are several limitations and uncertainties about the use of rhGH for children with ISS, which should be incorporated into decisions about whether to treat an individual child (see 'Decision to treat' above):

•Limited efficacy – Therapy with rhGH typically yields only modest gains in height compared with no treatment (an increase in adult height of approximately 4 to 6 cm), and adult height will usually be below average despite therapy (table 2). There is wide interindividual variation in height outcomes, including no increase in adult height for some patients. Although outcomes are not readily predictable, older age, shorter stature, and shorter parental height at rhGH initiation are correlated with lower efficacy. When rhGH treatment is contemplated, it is critical for the provider to discuss realistic expectations with the child and family. (See 'Height outcomes' above and 'Expectations' above.)

•Psychosocial considerations – Among children referred for treatment, parents often report psychosocial concerns, but studies generally show normal self-esteem, psychosocial functioning and quality of life among most children with ISS. Furthermore, several small studies failed to demonstrate an improvement in quality of life with rhGH treatment and some have speculated that rhGH could plausibly have adverse psychosocial effects because it draws their attention to their short stature. Nonetheless, individual patients may experience detrimental psychosocial effects of short stature, and efforts should be made to objectively assess this factor for each patient. (See 'Psychosocial considerations' above.)

•Treatment burdens – Burdens of treatment with rhGH include high costs and the need for subcutaneous injections, which are typically given daily for up to a decade. (See 'Costs' above.)

●Our approach – We suggest not treating children with ISS with rhGH unless there is compelling evidence supporting concerns of current or future adverse psychosocial consequences related to short stature (Grade 2C). This suggestion assumes that the possible psychosocial benefits associated with a modest increment in growth do not outweigh the cost and burden to the child of long-term therapy. (See 'Psychosocial considerations' above.)

●Dosing and duration – When rhGH treatment is chosen for children with ISS, we suggest a dosing scheme that adjusts doses based on insulin-like growth factor 1 (IGF-1) levels, similar to that used for children with GH deficiency (Grade 2C). We use a starting dose of rhGH of 0.24 to 0.3 mg/kg/week (35 to 43 mcg/kg/day), given once daily by subcutaneous injection. We then titrate up or down as needed, with a goal of keeping the serum IGF-1 concentration at approximately 1 SD above the mean for age and sex (upper limit 2 SD above the mean). We continue rhGH treatment only if the height velocity increases by at least 2.5 cm/year above the baseline height velocity when reassessed after one year of treatment. Treatment is continued until the height velocity slows to less than 2.0 to 2.5 cm/year in late puberty. (See 'Dosing' above and 'Dose adjustment for IGF-1 levels' above.)

●Other treatments for selected patients

•Patients with low baseline IGF-1 – Children with ISS and low baseline IGF-1 levels may have relative GH insensitivity (sometimes known as "partial IGF-1 deficiency"), provided that other causes of low IGF-1 such as inadequate nutrition have been excluded. If the family desires rhGH therapy for such children, we offer a six-month trial of rhGH treatment to determine their responsiveness. If growth does not accelerate significantly during the treatment trial, then we do not continue treatment. In this case, treatment with recombinant rhIGF-1 might be considered. (See 'Endocrine findings' above and 'Other treatments' above.)

•Boys with growth delay – Treatment with testosterone is an option for boys with features of constitutional delay of growth and puberty (CDGP), ie, with mild or moderate short stature and delayed puberty and bone age but with predicted adult height in the normal range for the family. Testosterone increases height velocity and promotes pubertal development but does not increase adult height. (See 'Testosterone' above.)