Medical Policy

Policy Num:      05.001.005
Policy Name:    Off Label Use of Human Growth Hormone
Policy ID:          [05.001.005]  [Ac / B / M+ / P+]  [5.01.06]

Last Review:     November 17, 2025
Next Review:     November 20, 2026
 

Related Policies: None

Off Label Use of Human Growth Hormone

Summary

Description

Recombinant human growth hormone (GH) is approved by the U.S. Food and Drug Administration (FDA) for various indications and is also proposed for various off-label indications, such as cystic fibrosis and treatment of older adults without documented growth hormone deficiency (GHD). This evidence review will focus specifically on various off-label indications to evaluate the net health outcome when human growth hormone is used compared with the standard therapy for these conditions.

Summary of Evidence

For individuals who have severe burns who receive human growth hormone (GH), the evidence includes randomized controlled trials (RCTs) and a meta-analysis. Relevant outcomes are symptoms, hospitalizations, and treatment-related morbidity. The meta-analysis found significantly shorter healing times and significantly shorter hospital stays with GH therapy when compared with placebo. Several RCTs have found significantly greater height gain in children with burns who received GH therapy versus placebo or no treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have altered body habitus related to antiretroviral therapy for HIV infection who receive human GH, the evidence includes a RCT and case series. Relevant outcomes are functional outcomes, quality of life (QOL), and treatment-related morbidity. The RCT measured the effect of low-dose GH on intermediate outcomes (inflammation markers). Case series data are insufficient for drawing conclusions about the impact of GH treatment on health outcomes in patients with HIV with altered body habitus due to antiretroviral therapy. Controlled studies reporting relevant outcomes are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have “genetic potential” (ie, lower than expected height percentiles based on parents’ height), no clinical trials evaluating GH therapy were identified. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have precocious puberty who receive human GH plus gonadotropin-releasing hormone (GnRH), the evidence includes a meta-analysis and a RCT. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. While the meta-analysis included RCTs and controlled trials, only 1 RCT and 4 controlled trials provided data for the meta-analysis informing final height, the difference in final height and targeted height, and height gain. The meta-analysis reported statistically significant gains of several centimeters for patients who received the combination therapy for at least 1 year compared with patients receiving GnRH alone. However, no studies have reported on the impact of short stature on functional or psychological outcomes in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are older adults with age-related GH deficiency (GHD) who receive human GH, the evidence includes a systematic review. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. The systematic review concluded there is a lack of evidence that GH therapy in older adults improves health outcomes. No subsequent controlled studies were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have cystic fibrosis (CF) who receive human GH, the evidence includes RCTs and systematic reviews. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. The RCTs were heterogeneous and reported various outcomes. Most of the systematic reviews did not pool results for outcomes such as frequency of intravenous antibiotic treatment, QOL, and bone fracture. The single pooled outcome in 1 systematic review (number of hospitalizations) was significantly lower in patients receiving GH therapy versus no treatment or placebo. Across trials, GH was found to improve intermediate outcomes such as height and weight; however, clinically meaningful outcomes relating to lung function were not consistently improved with GH. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to evaluate the net health outcome when human growth hormone is used to treat various off-label indications compared with the net health outcome achieved by standard therapy for these conditions.

Policy statements

Off-label use of recombinant human growth hormone (GH) therapy may be considered medically necessary for the following individuals (see specific patient selection criteria in the Policy Guidelines section):

• Promotion of wound healing in individuals with burns

• Prevention of growth delay in children with severe burns

Recombinant human growth hormone is considered investigational for all other off-label applications including, but not limited to the following:

• Treatment of altered body habitus (eg, buffalo hump) associated with antiviral therapy in HIV-infected individuals

• Constitutional delay (lower than expected height percentiles compared with target height percentiles and delayed skeletal maturation when growth velocities and rates of bone age advancement are normal)

• Treatment of children with “genetic potential” (ie, lower than expected height percentiles based on parents’ height)

• In conjunction with gonadotropin-releasing hormone analogs as a treatment of precocious puberty

• Growth hormone therapy in older adults without proven deficiency

• Treatment of cystic fibrosis

• Anabolic therapy (except for AIDS) provided to counteract acute or chronic catabolic illness (eg, surgery outcomes, trauma, cancer, chronic hemodialysis, chronic infectious disease) producing catabolic (protein wasting) changes in both adult and pediatric individuals

• Anabolic therapy to enhance body mass or strength for professional, recreational, or social reasons

• Glucocorticoid-induced growth failure

• Short stature due to Down syndrome

• Treatment of obesity

• Treatment of idiopathic dilated cardiomyopathy

• Treatment of juvenile idiopathic or juvenile chronic arthritis.

Policy Guidelines

The guidelines below correspond to the indications in the Policy section above.

Medically Necessary Indications

Burns

Growth hormone (GH) therapy for individuals with burns should be limited to individuals with third-degree burns.

Children with severe burns have been successfully treated with recombinant GH 0.05 to 0.2 mg/kg/d during acute hospitalization and for up to 1 year after a burn.

Investigational Indications

Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection

Research has evaluated the use of GH for altered body habitus, which may be a complication of antiretroviral therapy for HIV infection. Body habitus changes also referred to as fat redistribution syndrome or HIV-associated lipodystrophy syndrome, include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement, or an increased dorsocervical fat pad (“buffalo hump”) [Lo et. al., 2015; PMID 9525364]. There is relatively little published literature on the use of GH for this indication, mostly letters to editors and small case series.

Precocious Puberty

Precocious puberty is generally defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys. Central precocious puberty is related to hypothalamic-pituitary-gonadal activation, leading to an increase in sex steroid secretion, which accelerates growth and causes premature fusion of epiphyseal growth plates, thus impacting final height. Children with precocious puberty are often treated with gonadotropin-releasing hormone analogs to suppress the pituitary-gonadal activity, to slow the advancement of bone age, and to improve adult height.

Older Adults with Age-Related Growth Hormone Deficiency

Older adults may experience an age-related decline in GH, which can lead to increases in body fat and reductions in lean body mass and exercise capacity. However, until more safety and efficacy data are available, GH therapy is not recommended for otherwise endocrinologically-normal older adults for the purpose of delaying or reversing aging.

Cystic Fibrosis

Cystic fibrosis is a progressive, genetic disorder that primarily affects lung function and the digestive system. Poor linear growth and difficulty with weight gain due to chronic malnutrition are common among children with cystic fibrosis.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Human growth hormone may be adjudicated under the Drug Benefit as an injectable. State or federal mandates may require coverage eligibility for drugs used according to their labeled U.S. Food and Drug Administration indications. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Growth Hormone

Human growth hormone (GH), also known as somatotropin, is synthesized in somatotropic cells of the anterior lobe of the pituitary gland. Growth hormone deficiency (GHD) can occur for various conditions, such as:

• Pituitary tumor

• Pituitary dysfunction due to prior surgery or radiotherapy

• Extra-pituitary tumor

• Sarcoidosis and/or other infiltrating disorders

• Idiopathic

Growth hormone deficiency in children is manifested primarily by short stature. In adults, as well as in some children, other abnormalities associated with GHD are often evident. They include changes in body composition, higher levels of low-density lipoprotein cholesterol, lower bone density, and a decreased self-reported quality of life compared with healthy peers. Some evidence has suggested that there may be increases in cardiovascular disease and overall mortality, but it is less clear whether GHD causes these outcomes.

While human GH is approved by the US Food and Drug Administration (FDA) for various indications (see Table 1), this review will focus only on select off-label indications for human GH.

Outcome Measures in Growth Hormone Research

The most common outcome measure reported in GH research is a change in height. For some situations, such as in patients with documented GHD or genetic disorder and short stature, improvements in height alone may be a sufficient outcome measure. However, in most situations, a change in height is not in itself sufficient to demonstrate that health outcomes are improved. There is insufficient evidence to establish that short stature is associated with substantial impairments in psychological functioning or quality of life, or that increases in height improve these parameters. Similarly, improvements in other measures of body composition (eg, muscle mass, muscle strength) are not in themselves sufficient to establish that health outcomes are improved. Therefore, for most conditions in this evidence review, changes in other outcome measures, (eg, functional status, quality of life, disease-specific clinical outcomes) are necessary to demonstrate an improvement in health outcomes.

Regulatory Status

Several formulations of human GH have received FDA approval for various indications (Table 1). This evidence review has been modified as of September 2024 to focus only on select off-label indications. Table 2 provides a summary of recognized on-label uses and supporting references, previously included in the evidence review. These indications will not be addressed further within the evidence review.

Table 1. U.S. Food and Drug Administration Approved Indications by Product

 GH: growth hormone; GHD: growth hormone deficiency; SDS: standard deviation score; SHOX; short stature homeobox-containing gene.
^a In 2015, FDA approved a name change for Tev-Tropin; Tev-Tropin is now known as Zomacton.

Table 2. U.S. Food and Drug Administration Approved Indications and Supporting References

 GH: growth hormone; GHD: growth hormone deficiency; SHOX; short stature homeobox-containing gene.

Rationale

The evidence review was created in November 1997 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through September 10, 2025.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical uses of the technology in the intended population, and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Safety of Growth Hormone Treatment

Adverse events can occur with growth hormone (GH) treatment. In children, increased rates of skeletal problems (eg, worsening of scoliosis) can occur in association with a rapid growth spurt. In adults, arthralgias, myalgia, headache, edema, and carpal tunnel syndrome are common. Less common adverse events include pancreatitis and gynecomastia.^50,51,52, There is also concern that GH treatment may increase the rate of malignancy, particularly de novo leukemia, in patients without risk factors. However, to date, there is insufficient evidence of a causative relation between GH treatment and malignancy rates.

Johannsson et al (2022) published long-term observational results from the KIMS cohort of the Pfizer International Metabolic Database.^53, Mean follow-up among the 15,809 patients treated with Genotropin was 5.3 years. Treatment-related adverse events occurred in 18.8% of patients. The risk of de novo cancer was not increased compared to the general population (standard incidence ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.01) regardless of whether growth hormone deficiency (GHD) was adult-onset or childhood-onset.

Beck-Peccoz et al (2020) evaluated malignancy risk in adults with GHD undergoing long-term treatment with Omnitrope in the ongoing Patients Treated with Omnitrope (PATRO) Adults postmarketing surveillance study.^54, PATRO Adult included 1293 patients as of July 2018 from 76 sites in 8 European countries; enrollees who received ≥1 dose of Omnitrope were included in the safety population. Of these patients, 33 developed on-study malignancies (2.6%; incidence rate of 7.94 per 1000 patient-years) with tumors occurring after a mean of 79.4 months of GH treatment overall. Seven patients experienced >1 malignancy occurrence (n=41 total malignancies). Of the 33 patients, 3 had no prior medical history of malignancies or tumors. The most commonly occurring malignancies included basal cell carcinoma (n=13), prostate (n=6), breast (n=3), kidney (n=3), and malignant melanoma (n=3) and the majority occurred in patients >50 years of age (35 out of 41 cases). Growth hormone treatment was discontinued following malignancy diagnosis in 15 patients. Backeljauw et al (2022) published results of the analogous PATRO Children study.^55, Among 294 children enrolled in the United States and 6206 children enrolled internationally, treatment-related adverse events were rare (1.7% of patients in the United States, 7.3% of patients internationally). No cancers were considered related to treatment and no hyperglycemia/diabetes mellitus events were reported.

Thomas-Teinturier et al (2020) assessed the impact of GH treatment on the risk of secondary neoplasm in a French cohort of survivors of childhood cancer treated before 1986 (N=2852).^56, At a median follow-up of 26 years, 196 survivors were administered GH therapy during childhood or adolescence. A total of 374 patients developed at least 1 secondary neoplasm with 40 of these occurring after GH treatment. Results revealed that GH therapy did not increase the risk of secondary non-meningioma brain tumors (relative risk [RR], 0.6; 95% CI, 0.2 to 1.5; p=.3), secondary non-brain cancer (RR, 0.7; 95% CI, 0.4 to 1.2; p=.2), or meningioma (RR, 1.9; 95% CI, 0.9 to 4; p=.09).

Swerdlow et al (2017) published results from the Safety and Appropriateness of Growth Hormone Treatments in Europe study, which compared the risk of cancer mortality and cancer incidence among patients receiving GH therapy with national population rates.^57, For the cancer mortality analysis, the cohort consisted of 23,984 patients from 8 European countries. For the cancer incidence analysis, only those patients from countries with highly complete cancer registries (Belgium, Netherlands, Sweden, Switzerland, United Kingdom) were included (n=10,406). Over 50% received GH treatment due to “isolated growth failure,” defined as GHD, idiopathic short stature, and prenatal growth failure. Other common diagnoses leading to GH treatment included: Turner syndrome, pituitary hormone deficiency, and central nervous system tumor. For the cancer mortality cohort, mean follow-up was 17 years, mean age at follow-up was 27 years, and there were 251 cancer deaths. For the cancer incidence cohort, mean follow-up was 15 years, mean age at last follow-up was 26 years, and there were 137 incident cancers. For patients whose initial diagnosis was “isolated growth failure,” overall cancer risk was not elevated. For patients whose initial diagnosis was not cancer, neither cancer mortality nor cancer incidence was related to the age of treatment initiation and duration of treatment.

Several publications on the safety of GH therapy have used French registry data and vital statistics. Analysis of long-term mortality after GH treatment was conducted by Carel et al (2012).^58, A total of 6928 children were included in the study. Indications for GH therapy included idiopathic isolated GHD (n=5162), neurosecretory dysfunction (n=534), idiopathic short stature (n=871), and born small for gestational age (n=335). The mean dose of GH used was 25 μg/kg/d, and the mean treatment duration was 3.9 years. Patients were followed for a mean of 17.3 years. As of September 2009, follow-up data on vital status were available for 6558 (94.7%) of participants. Ninety-three (1.42%) of the 6558 individuals had died. The mortality rate was significantly higher in patients treated with GH than would be expected on the basis of year, sex, or age (standardized mortality ratio, 1.33; 95% CI, 1.08 to 1.64). Examination of the causes of death found a significant increase in mortality due to circulatory system diseases. In addition, there was a significant increase in the number of deaths due to bone tumors (3 observed deaths vs. 0.6 expected deaths) but no other types of cancers or overall cancer deaths. There was also a significant increase in the number of deaths due to cerebral or subarachnoid hemorrhage: 4 observed deaths versus 0.6 expected.

Poidvin et al (2014) reported on the same data, focusing on the risk of stroke in adulthood among childhood users of GH therapy.^59, This analysis included 6874 children with idiopathic isolated GHD or short stature; the mean length of follow-up was 17.4 years. There were 11 (0.16%) validated cases of stroke and the mean age at the time of stroke was 24 years. Risk of stroke was significantly higher in adults who had used GH than in general population controls. Stroke risk was also compared with general population controls. Standard incidence ratios were 2.2 (95% CI, 1.3 to 3.6) compared with registry data from Dijon and 5.3 (95% CI, 3.0 to 8.5) using Oxford registry data. The increased risk was largely for hemorrhagic stroke (8/11 cases), and this elevated risk persisted when the 3 patients who had been small for gestational age were excluded from the analysis. In all of the analyses from this research team, there were a small number of events (ie, deaths or stroke), and thus conclusions from these data are not definitive on the long-term safety of GH therapy.

Tidblad et al (2021) evaluated the potential association between childhood GH treatment and long-term cardiovascular morbidity via a nationwide population-based cohort study of Swedish patients treated with GH during childhood from January 1985 to December 2010 for GHD, small for gestational age, or idiopathic short stature (n=3408).^60, Data on outcomes of interest were prospectively collected from January 1985 through December 2014. For each case, 15 controls matched for sex, birth year, and geographical region were randomly selected from the Swedish Total Population Register (N =50,036). The primary outcome was the initial cardiovascular event recorded after the start of follow-up. Results revealed that a total of 1809 cardiovascular events were recorded during follow-up. The crude incidence rates were 25.6 (95% CI, 21.6 to 30.4) events per 10,000 person-years among GH patients and 22.6 (95% CI, 21.5 to 23.7) events per 10,000 person-years among controls. Among male patients and controls, the incidence rates were similar. However, the rate was higher in female GH patients than in female controls (31.2 events per 10,000 person-years vs. 23.2 events per 10,000 person-years). The authors concluded that GH treatment during childhood was associated with increased risks of cardiovascular events in early adulthood, particularly in women. However, a causal association is not definitively established and the absolute risk remains low.

Nonrandomized Studies

Population Reference No. 1

Severe Burns

Clinical Context and Therapy Purpose

The purpose of human GH is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with severe burns.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with severe burns.

Interventions

The therapy being considered is human GH to treat or to prevent growth delay.

Comparators

The following practice is currently being used to treat or prevent growth delay due to severe burns: standard wound care. Typical treatment for severe burns includes skin transplantation and grafting.

Outcomes

The general outcomes of interest are symptoms, hospitalizations, and treatment-related morbidity. Follow-up at 2 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Treatment of Severe Burns

Systematic Reviews

A Cochrane review by Breederveld et al (2012) included RCTs evaluating the impact of GH therapy on the healing rates of burn wounds.^61, Thirteen trials were identified that compared GH therapy with another intervention or to placebo. Six included only children and 7 involved only adults. Twelve studies were placebo-controlled. Findings of 2 studies reporting wound healing time in days were pooled. The mean healing time was significantly shorter in the GH-treated group than in the placebo group (mean difference [MD], -9.07 days; 95% CI, -4.39 to -13.76 days). Reviewers also performed meta-analyses of studies that did not conduct survival analyses but did follow patients until their wounds healed. These analyses found significantly shorter healing time in patients who received GH therapy among adults (2 studies) and children (2 studies). A pooled analysis of 5 studies did not find a statistically significant difference in mortality among patients receiving GH therapy and placebo (RR, 0.53; 95% CI, 0.22 to 1.29). The mortality analysis likely was underpowered; the total number of deaths was 17. A pooled analysis of 3 studies involving adults found significantly shorter hospital lengths of stay in patients who received GH therapy compared with placebo (MD, -12.55 days; 95% CI, -17.09 to -8.00 days). In another pooled analysis, there was a significantly higher incidence of hyperglycemia in GH-treated patients than in controls (RR, 2.65; 95% CI, 1.68 to 4.16).

Randomized Controlled Trials

A RCT by Knox et al (1995) measuring mortality included 54 adult burn patients who survived the first 7 postburn days.^62, Those patients showing difficulty with wound healing were treated with human GH and compared with those healing at the expected rate with standard therapy. The mortality rate of GH-treated patients was 11% compared with 37% for those not receiving GH (p=.027). Infection rates were similar in both groups.

Singh et al (1998) studied 2 groups of patients (N=22) with comparable third-degree burns; those who received GH had improved wound healing and a lower mortality rate (8% vs. 44%).^63, A placebo-controlled trial by Losada et al (2002) found no benefit to GH with regard to the length of hospitalization in 24 adults with severe burns.^64,

Prevention of Growth Delay in Children With Severe Burns

Children with severe burns show significant growth delays for up to 3 years after injury. Growth hormone treatment in 72 severely burned children for 1 year after discharge from intensive care resulted in a significantly increased height in a placebo-controlled, randomized, double-blind trial.^65, Aili Low et al (2001) also found that GH treatment in severely burned children during hospitalization resulted in significantly greater height velocity during the first 2 years after a burn compared with a similar group of untreated children.^66,

Section Summary: Severe Burns

For individuals who have severe burns who receive human GH, the evidence includes RCTs and a meta-analysis. The meta-analysis found significantly shorter healing times and significantly shorter hospital stays with GH therapy than with placebo. Several RCTs have found significantly greater height gain in children with burns who received GH therapy versus placebo or no treatment.

For individuals who have severe burns who receive human growth hormone (GH), the evidence includes randomized controlled trials (RCTs) and a meta-analysis. Relevant outcomes are symptoms, hospitalizations, and treatment-related morbidity. The meta-analysis found significantly shorter healing times and significantly shorter hospital stays with GH therapy when compared with placebo. Several RCTs have found significantly greater height gain in children with burns who received GH therapy versus placebo or no treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Altered Body Habitus Related to Antiretroviral Therapy for Human Immunodeficiency Virus Infection

Clinical Context and Therapy Purpose

The purpose of human GH is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with altered body habitus related to antiretroviral therapy for HIV infection.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with altered body habitus related to antiretroviral therapy for HIV infection.

Interventions

The therapy being considered is human GH.

Comparators

The following practice is currently being used to treat altered body habitus due to antiretroviral therapy for HIV infection: standard care without human GH treatment.

Outcomes

The general outcomes of interest are functional outcomes, QOL, and treatment-related morbidity. Treatment of 40 weeks is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Because high-dose GH has been associated with adverse events relating to inflammation, Lindboe et al (2016) conducted a randomized, double-blind, placebo-controlled trial to test the effect of low-dose GH in the treatment of HIV-infected patients on antiretroviral therapy.^67, Participants were randomized to GH 0.7 mg/day (n=24) or placebo (n=18) for 40 weeks. The primary outcome was change in inflammation measured by C-reactive protein and soluble urokinase plasminogen activator receptor, both of which increase with inflammation. After 40 weeks, low-dose GH significantly lowered C-reactive protein. Low-dose GH lowered soluble urokinase plasminogen activator receptors as well, but the difference was not statistically significant, even after controlling for age, weight, smoking status, and lipodystrophy.

Case Series

A case series was reported by Wanke et al (1999) who treated 10 HIV-infected patients with fat redistribution syndrome with GH for 3 months.^68, The authors reported improved waist/hip ratio and mid-thigh circumference.

Section Summary: Altered Body Habitus Related to Antiretroviral Therapy for Human Immunodeficiency Virus Infection

For individuals who have altered body habitus related to antiretroviral therapy for HIV infection who receive human GH, the evidence includes a RCT and case series. The RCT measured the effect of low-dose GH on intermediate outcomes (inflammation markers). Case series data are insufficient for drawing conclusions about the impact of GH treatment on health outcomes in HIV-infected patients with altered body habitus due to antiretroviral therapy. Controlled studies reporting relevant outcomes are needed.

For individuals who have altered body habitus related to antiretroviral therapy for HIV infection who receive human GH, the evidence includes a RCT and case series. Relevant outcomes are functional outcomes, quality of life (QOL), and treatment-related morbidity. The RCT measured the effect of low-dose GH on intermediate outcomes (inflammation markers). Case series data are insufficient for drawing conclusions about the impact of GH treatment on health outcomes in patients with HIV with altered body habitus due to antiretroviral therapy. Controlled studies reporting relevant outcomes are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Children With “Genetic Potential”

Clinical Context and Therapy Purpose

The purpose of human GH is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with “genetic potential”.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with “genetic potential”.

Interventions

The therapy being considered is human GH.

Comparators

The following practice is currently being used to treat children with “genetic potential”: standard care without human GH treatment.

Outcomes

The general outcomes of interest are functional outcomes, QOL, and treatment-related morbidity. Due to the lack of relevant data, it is not possible to determine an appropriate window for follow-up.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Clinical Studies

No randomized or nonrandomized studies were identified that have evaluated the efficacy, safety, and/or psychosocial impacts of treating children with “genetic potential” (i.e., children with lower than expected height percentiles based on their parents’ height).

Section Summary: Children With “Genetic Potential”

For individuals who have “genetic potential” (ie, lower than expected height percentiles based on parents’ height), no clinical trials evaluating GH therapy were identified. There is insufficient evidence to draw conclusions about the use of human GH to treat “genetic potential.”

For individuals who have “genetic potential” (ie, lower than expected height percentiles based on parents’ height), no clinical trials evaluating GH therapy were identified. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Precocious Puberty

Clinical Context and Therapy Purpose

The purpose of human GH is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with precocious puberty.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is children with precocious puberty.

Interventions

The therapy being considered is human GH plus gonadotropin-releasing hormone (GnRH).

Comparators

The following practice is currently being used to treat precocious puberty: GnRH only.

Outcomes

The general outcomes of interest are functional outcomes, QOL, and treatment-related morbidity. Follow-up at 2 years is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Liu et al (2016) published a meta-analysis comparing GnRH with the combination therapy of GH plus GnRH for the treatment of females who had idiopathic central precocious puberty.^69, The literature search, conducted through December 2014, identified 6 RCTs (n=162) and 6 clinical controlled trials (n=247) for inclusion. Risk of bias in the RCTs was assessed using the Cochrane Collaboration checklist. Five of the RCTs were determined to have a moderate risk of bias and 1 trial had a high-risk of bias. The controlled trials were assessed using the Methodological Index for Nonrandomized Studies, based on 12 items, with an ideal global score of 24. Scores on the Methodological Index for Nonrandomized Studies for the 6 controlled trials ranged from 17 to 20 because none of the trials reported blinded outcome evaluation or prospective calculation of study size. Primary outcomes included final height, the difference between final height and targeted height, and height gain. Among the 12 included studies, the age of participants ranged from 4.6 to 12.2 years and treatment with the combination therapy ranged from 6 months to 3 years. One RCT and 4 controlled trials provided data for the meta-analyses. Results showed that patients receiving the combination therapy for at least 1 year experienced significantly greater final height, the difference in final height and targeted height, and height gain compared with those receiving GnRH alone (MD, 2.8 cm; 95% CI, 1.8 to 3.9 cm; MD, 3.9 cm; 95% CI, 3.1 to 4.7 cm; MD, 3.5 cm; 95% CI, 1.0 to 6.0 cm, respectively). When treatment duration was less than 1 year, no significant differences in height outcomes were found.

Randomized Controlled Trials

One RCT compared GnRH analogs alone with GnRH analogs plus GH therapy. This trial, by Tuvemo et al (1999), included 46 girls with precocious puberty.^70, Criteria for participation did not include predicted adult height or growth velocity. After 2 years of treatment, mean growth and predicted adult height were greater in those receiving combined treatment than in those receiving GnRH analogs alone. The absence of final height data limited interpretation of this trial.

Section Summary: Precocious Puberty

For individuals who have precocious puberty who receive human GH plus GnRH, the evidence includes a meta-analysis and a RCT. While the meta-analysis included RCTs and controlled trials, only 1 RCT and 4 controlled trials provided data for the meta-analysis informing final height, the difference in final height and targeted height, and height gain. The meta-analysis reported statistically significant gains of several centimeters for patients who received the combination therapy for at least 1 year compared with patients receiving GnRH alone. However, no studies have reported on the impact of short stature on functional or psychological outcomes in this population.

For individuals who have precocious puberty who receive human GH plus gonadotropin-releasing hormone (GnRH), the evidence includes a meta-analysis and a RCT. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. While the meta-analysis included RCTs and controlled trials, only 1 RCT and 4 controlled trials provided data for the meta-analysis informing final height, the difference in final height and targeted height, and height gain. The meta-analysis reported statistically significant gains of several centimeters for patients who received the combination therapy for at least 1 year compared with patients receiving GnRH alone. However, no studies have reported on the impact of short stature on functional or psychological outcomes in this population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Older Adults with Age-related Growth Hormone Deficiency

Clinical Context and Therapy Purpose

The purpose of human GH is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals who are older adults with age-related GHD.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is older adults with age-related GHD.

Interventions

The therapy being considered is human GH.

Comparators

The following practice is currently being used to treat older adults with age-related GHD: standard care without human GH treatment.

Outcomes

The general outcomes of interest are functional outcomes, QOL, and treatment-related morbidity. Due to the lack of relevant data, it is not possible to determine the window for follow-up.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A TEC Assessment (2001) investigated the use of GH in older adults with age-related GHD and concluded that there was insufficient evidence of efficacy.^71, It is not possible to prove the effectiveness of GH treatment or lack thereof unless otherwise similar groups of treated versus nontreated patients are compared over a sufficient length of time to allow detection of any significantly and clinically different results.

Section Summary: Older Adults With Age-Related Growth Hormone Deficiency

For individuals who are older adults with age-related GHD who receive human GH, the evidence includes a systematic review (TEC Assessment). The TEC Assessment concluded there is a lack of evidence that GH therapy in older adults improves health outcomes. No subsequent controlled studies were identified.

For individuals who are older adults with age-related GH deficiency (GHD) who receive human GH, the evidence includes a systematic review. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. The systematic review concluded there is a lack of evidence that GH therapy in older adults improves health outcomes. No subsequent controlled studies were identified. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 6

Cystic Fibrosis

Clinical Context and Therapy Purpose

The purpose of human GH is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with cystic fibrosis (CF).

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with CF.

Interventions

The therapy being considered is human GH.

Comparators

The following practice is currently being used to treat CF: standard care without human GH treatment.

Outcomes

The general outcomes of interest are functional outcomes, QOL, and treatment-related morbidity. Treatment of 1 year is of interest to monitor outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A Cochrane review by Thaker et al (2013) evaluated GH therapy for improving lung function, nutritional status, and QOL in children and young adults with CF.^72, Reviewers identified 4 RCTs (N=161). All studies used daily subcutaneous injection of human GH as the intervention and included a no treatment or a placebo control group. All trials measured pulmonary function and nutritional status. Due to differences in how outcomes were measured, study findings were not pooled. Across trials, GH improved intermediate outcomes such as height and weight; however, improvements in lung function were inconsistent. No significant changes in QOL or clinical status were detected.

An update to the Cochrane review by Thaker et al was published in 2018.^73, Eight trials (291 participants) were included in the revision, of which 7 compared standard-dose recombinant human growth hormone (rhGH; approximately 0.3 mg/kg/week) to no treatment, and a 3-arm trial (63 participants) compared placebo, standard-dose rhGH (0.3 mg/kg/week) and high-dose rhGH (0.5 mg/kg/week). Results showed that patients receiving rhGH demonstrated modest improvement in height, weight, and lean body mass between 6 and 12 months, but there was no consistent evidence that rhGH improved lung function, muscle strength, or QOL. A subsequent review in 2021 did not find any new studies to add, and the authors concluded that further randomized trial data is needed to justify routine clinical use.^74,

Previously, a systematic review by Phung et al (2010) identified 10 controlled trials evaluating GH for treating patients with CF.^75, One study was placebo-controlled, 8 compared GH therapy with no treatment, and the remaining trial compared GH alone with glutamine or glutamine plus GH. Treatment durations ranged from 4 weeks to 1 year. There were insufficient data to determine the effect of GH on most health outcomes (eg, frequency of intravenous antibiotic treatment, QOL, bone fracture). Data were pooled for a single outcome, frequency of hospitalizations. In trials lasting at least 1 year, there were significantly lower rates of hospitalizations per year in groups receiving GH therapy (pooled effect size, -1.62 events per year; 95% CI, -1.98 to -1.26 events per year).

Randomized Controlled Trials

An industry-sponsored, open-label RCT was published by Stalvey et al (2012).^76, It compared GH therapy with no treatment in prepubertal children with CF younger than 14 years of age. Eligibility criteria included height at or under the 10th percentile for age and sex; children with documented GHD were excluded. Participants were treated daily for 12 months and followed for another 6 months. The trial included 68 children; 62 (91%) were included in the efficacy analysis, and all but 1 were included in the safety analysis. The annualized height velocity at month 12 was 8.2 cm/y in the treatment group and 5.3 cm/y in the control group (p<.001). The mean height standard deviation score (SDS) in the treatment group was -1.8 at baseline, -1.4 at 12 months, and -1.4 at 18 months versus -1.9 at all 3 time points in the control group. The change in mean height SDS from baseline to 12 months was significantly greater in the treatment than in the control group (p<.001). Between months 12 and 18, the control group remained at the same height SDS, while the treatment group experienced a slight decline (0.1 SDS), but maintained a 0.5 SDS advantage over the control group.

In terms of pulmonary outcomes, the unadjusted rate of change from baseline to 12 months for most variables (7 of 8 pulmonary test results) did not differ between groups. However, the unadjusted change from 12 to 18 months (after treatment ended) was significantly greater in the control group than in the treatment group for 4 of 7 pulmonary test variables, including forced expiratory volume in 1 second (p<.005) and forced vital capacity (p<.01). In the treatment group, mean forced expiratory volume in 1 second was 1209 L at baseline, 1434 L at 12 months, and 1467 L at 18 months compared with 1400 L at baseline, 1542 L at 12 months, and 1674 L at 18 months in the control group. From baseline to 12 months, the between-group difference in change in the 6-minute walk distance did not differ significantly (26.3 meters; 95% CI, -44.8 to 97.4 meters). Ten children in the treatment group and 9 in the control group were hospitalized for pulmonary exacerbations during the 12-month trial; the difference between groups was not statistically significant. In general, treatment with GH resulted in statistically significant improvements in height SDS but did not significantly improve clinical outcomes associated with CF.

Section Summary: Cystic Fibrosis

For individuals who have CF who receive human GH, the evidence includes RCTs and systematic reviews. The RCTs were heterogeneous and reported various outcomes. Most of the systematic reviews did not pool results for outcomes such as frequency of intravenous antibiotic treatment, QOL, and bone fracture. The single pooled outcome in 1 systematic review (number of hospitalizations) was significantly lower in patients receiving GH therapy versus no treatment or placebo. Across trials, GH was found to improve intermediate outcomes such as height and weight; however, clinically meaningful outcomes relating to lung function were not consistently improved with GH.

For individuals who have cystic fibrosis (CF) who receive human GH, the evidence includes RCTs and systematic reviews. Relevant outcomes are functional outcomes, QOL, and treatment-related morbidity. The RCTs were heterogeneous and reported various outcomes. Most of the systematic reviews did not pool results for outcomes such as frequency of intravenous antibiotic treatment, QOL, and bone fracture. The single pooled outcome in 1 systematic review (number of hospitalizations) was significantly lower in patients receiving GH therapy versus no treatment or placebo. Across trials, GH was found to improve intermediate outcomes such as height and weight; however, clinically meaningful outcomes relating to lung function were not consistently improved with GH. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Pediatrics

In 2016, the American Academy of Pediatrics published guidelines on the evaluation and referral of children with signs of early puberty.^77, The use of gonadotropin-releasing hormone analogs were discussed as treatment options, but growth hormone (GH) as a treatment option was not discussed.

American Association of Clinical Endocrinologists

Pediatric Endocrine Society

In 2015, the Pediatric Endocrine Society (PES) published an evidence-based report focusing on the risk of neoplasia in patients receiving growth hormone (GH) therapy.^78, The report concluded that GH therapy can be administered without concerns about the impact on neoplasia in children without known risk factors for malignancy. For children with medical conditions associated with an increased risk of future malignancies, patients should be evaluated on an individual basis and decisions made about the trade-off between a possible benefit of GH therapy and possible risks of neoplasm.

As an addendum to the 2015 guidelines, Grimberg and Allen (2017), guideline coauthors, published a historical review of the use of GH.^79, They asserted that although the guidelines did not find an association between GH and neoplasia, the use of GH should not necessarily be expanded. While the use of GH for patients with growth hormone deficiency (GHD) was recommended, evidence gaps persist in the use of GH for other indications such as idiopathic short stature and partial isolated GHD. No off-label indications were addressed.

National Institute of Health and Care Excellence

In 2010, the National Institute of Health and Care Excellence issued guidance on human GH for growth failure in children.^80, The Institute recommended GH as a possible treatment for children with growth failure with any of the following conditions:

• GHD

• Turner syndrome

• Prader-Willi syndrome

• Chronic renal insufficiency

• Small for gestational age and have growth failure at 4 years

• Short stature homeobox-containing gene (SHOX) deficiency.

There was no mention of its use in off-label indications.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

There are no currently, ongoing or unpublished trials that might influence this review as of September 2025.

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