Treating growth hormone deficiency

Treatments and guidelines for growth hormone deficiency

Recombinant human growth hormone (rhGH) remains the main pharmacologic treatment for growth hormone deficiency (GHD).¹

Traditionally, rhGH has been administered as a daily injection, but once-weekly long-acting growth hormone (LAGH) formulations are now approved in multiple regions for pediatric GHD, with some agents also approved for use in adult populations¹

In children, treatment aims to normalize height during childhood and support attainment of normal adult height.³ In adults, the main goal of treatment is to improve and reverse the metabolic symptoms of GHD and associated risks.⁴

Treatment with rhGH can have beneficial effects on:⁵

• Lipid profile
• Cardiac performance
• Body composition
• Bone mineral density

Daily recombinant human growth hormone treatment  

The pituitary gland produces and secretes natural GH; synthetic daily GH, somatropin, mimics naturally occurring hGH. Daily injections of GH have been available for treatment of GHD since 1985 and remain the standard of care.⁶ Daily GH is well tolerated and effective in both children and adults, with large numbers of patients assessed over the long-term.^6-11

However, there is variation in the clinical management of GH across the globe, with differing recognition of GHD, availability of GH, and reimbursement.^12,13

Daily GH is indicated for the treatment of children who have growth failure due to GHD and for adults with either childhood or adulthood onset of GHD^14-17

The European Medicines Agency (EMA) recommends that somatropin should not be used in patients showing tumor activity.¹⁸

Growth hormone treatment guidelines for children

The 2016 Pediatric Endocrine Society (US) Drug and Therapeutics Committee and Ethics Committee guidelines recommends an initial dose of 0.16–0.24 mg/kg per week (22–35 μg/kg per day), with individualization of subsequent dosing.¹⁹ The National Institute for Health and Care Excellence (NICE; TA188, UK) guidance recommends that the choice of daily GH treatment product should be a shared decision between the clinician and the patient and/or their carer.¹⁷ Daily GH treatment should be discontinued if:¹⁷

• Growth velocity increases less than 50% from baseline in the first year of treatment
• Final height is nearly reached, and growth velocity is less than 2 cm total growth in 1 year
• Adherence problems cannot be resolved
• Final height is attained

Growth hormone treatment guidelines for adults

NICE (TA188, UK) recommends daily GH treatment if adults:¹⁶

• Have severe GHD, defined as a peak GH response of less than 9 mU/L (3 ng/mL) during an insulin tolerance test or a cross-validated GH threshold in an equivalent test
• Have impaired quality of life (QoL), defined as a reported score of at least 11 on the QoL assessment of GHD in adults (QoL-AGHDA) questionnaire, which should be reassessed every 9 months
• Are already receiving treatment for any other pituitary hormone deficiencies

Figure 1 shows some of the common beneficial effects of GH replacement therapy in adults with GHD.

Figure 1. Primary beneficial effects of growth hormone replacement therapy in the treatment of adult growth hormone deficiency (Adapted).²⁰ BMD, bone mineral density; IMT, intima media thickness; LDL, low-density lipoprotein.

Growth hormone treatment during transition to adult care

For adolescents with persistent GHD during the transition to adult care, daily GH replacement therapy should continue to support:²²

• Ideal peak bone mass
• Satisfactory body composition
• Healthy lipid and glucose profiles
• Improved QoL

The American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines recommend continuing daily GH treatment after final height is achieved during the transition period.²³ NICE (UK) recommends that daily GH treatment should be stopped for 2–3 months before a reassessment of GHD status.¹⁶ If GHD is reconfirmed, adult doses can be given.¹⁶ During adolescence, a dose of 0.7 mg/kg per week is recommended by the Drug and Therapeutics, and Ethics Committees of the Pediatric Endocrine Society (US).¹⁹

To maximize the window of treatment opportunity in adolescents with GHD, researchers have used gonadotropin-releasing hormone analogues (GnRHa) to suppress or delay puberty, resulting in a larger height gain versus rhGH alone over 3 years of treatment.²⁴ GnRHa has also been widely used in clinical practice.²⁵ However, more research is needed in this area to fully determine the risks and benefits of using GnRHa in adolescents.²⁴

Long-acting growth hormone treatment

Daily rhGH treatment carries a substantial injection burden. To combat this, various formulations of LAGH have been prepared or are in development.^2,6

Several once-weekly LAGH formulations are now available, including lonapegsomatropin, somapacitan, and somatrogon, following pivotal phase 3 trials¹

A weekly injectable LAGH (somatrogon) was first approved in Canada in October 2021, and was approved by the EMA in February 2022 for the treatment of children and adolescents from 3 years of age.²⁶ The EMA recommends a dose of 0.66 mg/kg per week, adjusted as necessary.²⁶ Patients weighing more than 45 kg who require doses above 30 mg will receive the dose in two injections.²⁶

While there have been no new safety signals identified in short-term studies, the long-term safety and efficacy of LAGH preparations require further longitudinal research.^2,6 Unlike daily rhGH, LAGH does not replicate the daily spontaneous pulsatile secretion patterns of rhGH.²⁷ Long-term data are also needed to understand potential metabolic consequences.²⁷

Efficacy and safety of treatments for growth hormone deficiency

Efficacy of recombinant human growth hormone in children

Recombinant human growth hormone (rhGH) has been used in clinical practice for more than 30 years.²⁸ The U.S. Food and Drug Administration (FDA) first approved rhGH for pediatric growth hormone deficiency (GHD) in 1985, followed by the European Medicines Agency (EMA) in 1987.^5,29 A biosimilar of rhGH for pediatric GHD was first approved by the EMA in 2006 and the FDA in 2007.^28,30

In the long term, daily GH is well tolerated and effective in children^7,9,10

The Kabi/Pfizer International Growth Database (KIGS) study is a large international database (N=83,803) of children treated with rhGH in the real world.³¹ The baseline median height standard deviation score was –2.99 (–4.44 to –2.06) in boys with idiopathic GHD (IGHD; n=2,057), and –3.62 (–5.41 to –2.46) in girls with IGHD (n=1,186).³¹ Following treatment, the near adult height was –1.16 (–2.67 to 0.13) in boys and –1.47 (–3.07 to 0.07) in girls.³¹

Safety of recombinant human growth hormone in children

The safety of rhGH in children has been extensively investigated, driven in part by concerns about a theoretical increased risk of neoplasms.^5,32 Reported adverse events include:⁵

• Limb pain
• Myalgias
• Arthralgias
• Peripheral edema
• Injection site pain and reactions

Rare but more serious adverse effects include:⁵

• Intracranial hypertension
• Worsening of scoliosis
• Slipped capital femoral epiphysis
• Obstructive sleep apnea
• Pancreatitis

The SAGhE study assessed long-term mortality in 24,232 patients from eight European countries who were treated with rhGH during childhood, regardless of treatment duration.³³ It showed that treatment during childhood is unlikely to be associated with all-cause mortality, which was more closely linked to the underlying diagnosis.³³ In people with isolated GHD, there was no association with increased all-cause mortality and the mean daily or cumulative dose of rhGH.³³ There was no increase in mortality from neoplasms in this population.³³ The authors recommend long-term surveillance to detect potential risks later in life.³³

Although daily rhGH therapy is not associated with cancer mortality or cancer incidence, it may increase the risk of a second tumor in children previously treated for cancer.³⁴ A systematic review and meta-analysis showed significant increases in overall cancer standardized mortality ratios (2.74; 95% CI, 1.18–5.41) and the relative risk of neoplasms (1.99; 95% CI, 1.28–3.08; P=0.002).³⁵

Efficacy of long-acting growth hormone in children

Clinical trials have shown generally comparable efficacy between LAGH and daily GH; however, indirect comparative analyses suggest differences between individual LAGH formulations.^27,36 A systematic review and meta-analysis of rhGH treatment in children found no significant difference between high-dose LAGH and daily rhGH in height velocity.³⁶

In a phase 3 study investigating the efficacy and safety over 12 months of weekly somatrogon (an LAGH) versus daily somatropin in children with GHD, weekly somatrogon was noninferior to daily somatropin.³⁷

Safety of long-acting growth hormone in children

In the same phase 3 study, somatrogon and somatropin were both well tolerated, with mild–moderate TEAEs reported by 78.9% of patients in the somatrogon group and 79.1% in the somatropin group.³⁷

Some studies suggest additional safety concerns associated with LAGH, including the formation of neutralizing antidrug antibodies, which have the potential to decrease treatment response.³⁸ Therefore, there is a need for accurate and reliable antidrug antibody assays for LAGH.³⁸

In infants and young children with hypoglycemia associated with severe GHD, LAGH may pose an unnecessary risk.³⁸

IGF-1 serum levels increase with LAGH treatment.²⁷ While high levels of circulating IGF-1 have been associated with an increased cancer risk, there is no evidence of associated risks with transient IGF-1 elevations.²⁷ Long-term data will be needed to understand this potential relationship.²⁷

Maintaining IGF-1 levels within the normal range should be a goal in both LAGH and daily GH treatment²⁷

Epidemiologic studies have discussed potential long-term effects of GH, such as induction of neoplasm or development of diabetes.⁴ Long-term and real-world data for LAGH remain limited relative to daily GH, although follow-up data from clinical trials and emerging observational studies are increasing.⁴⁷

Safety of recombinant human growth hormone in adults

An international European post-marketing surveillance study evaluated the safety and effectiveness of a biosimilar daily GH in adults with GHD using data from the PATRO Adults study.⁸ Treatment-related adverse events (TEAEs) were reported in 8.1% of the 1,447 patients in the study.⁸ The most common TEAEs were:⁸

• Aching or pain in joints (n=19)
• Muscle pain (n=16)
• Headache (n=14)
• Peripheral edema (n=10)

The mean insulin-like growth factor I standard deviation score (IGF-I SDS) increased from −2.34 at baseline to −0.23 at 12 months and was relatively stable for up to 3 years (Figure 2).⁸ Body mass index was consistent between baseline and 3 years.⁸

Figure 2. Insulin-like growth factor standard deviation score (IGF-I SDS) over time in daily GH-naive patients (effectiveness population: a subset of the safety set consisting of all patients with a documented baseline visit) (Adapted).⁸ The shaded area represents the IGF-I target range. IGF-I, insulin-like growth factor I; SDS, standard deviation score.

An observational, long-term study of 1,293 adults with GHD showed that a somatropin biosimilar did not increase risk of glucose metabolism disorders or of malignancy.^39,40 An increased risk of new malignancies in patients who previously had cancer, however, cannot be excluded.⁴⁰ Guidelines from the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) state that daily GH therapy in patients with a history of active malignancy is contraindicated.²³ Although no data suggest that daily GH increases cancer risk in patients with no history of malignancy, long-term monitoring and standard cancer screening are recommended for patients receiving daily GH.²³

Risks and benefits of GHD treatment in adults

Table 1 presents a summary of the risks and benefits of growth hormone replacement therapy in adults.

Table 1. Long-term benefits and risks of growth hormone replacement therapy in adult patients with growth hormone deficiency (Adapted).⁴ BMI, body mass index; chol, cholesterol; CRP, C-reactive protein; GHD, growth hormone deficiency; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

To avoid potential side effects of GH, dosing should be individualized and monitored regularly.⁴ A 2018 review explored risks and benefits of treatment with GH replacement therapy in adults by addressing clinically relevant questions.⁴ Table 2 shows the best available responses to these questions based on the available evidence.⁴

Table 2. Questions and answers about growth hormone replacement therapy in adults with growth hormone deficiency (Adapted).^4,27,36,38 This information is a high-level summary. For full details, please refer to the source literature cited. These are findings of a systematic review and meta-analysis investigating efficacy and safety in children. GH, growth hormone; GHRT, growth hormone replacement therapy; IGF-1, insulin-like growth factor 1; LAGH, long-acting growth hormone; QoL, quality of life.

Treatment adherence and quality of life in growth hormone deficiency

Long-acting GH formulations have been developed to reduce treatment burden and improve patient adherence^2,6

Treatment burden, patient experience, safety, and efficacy should be considered when choosing treatments for growth hormone deficiency (GHD). Patient adherence can be an issue for GHD treatment due to forgetfulness, pain or discomfort, or being away from home.^35,41 Lower adherence is particularly observed in some subgroups, including female and African American patients.⁴¹ Adherence is multifactorial and can be affected by treatment availability and access.³⁸

Improving adherence could improve patient outcomes and lower healthcare costs.⁴¹ A study investigating a once-weekly injectable (somatrogon) versus a once-daily injectable (somatropin) in 87 pediatric patients found that once-weekly somatrogon had a lower treatment burden, as measured by the Dyad Clinical Outcome Assessment (DCOA), than somatropin over 12 weeks.⁴²

Reduced injection frequency is one of the main proposed advantages of LAGH. Consensus guidance suggests that this may improve adherence and treatment outcomes over time, particularly in patients with suboptimal adherence to daily GH.¹

With more treatment options now available for patients with GHD, treatment decisions should carefully assess the risk–benefit profile of each option, including serious treatment-emergent adverse events and patient quality of life.⁴³

Health economics of growth hormone deficiency treatment

The economic burden of treatment for growth hormone deficiency (GHD) remains substantial and is influenced by treatment regimen, adherence, and healthcare setting⁴⁴

It is estimated that a complete multiyear course of treatment for GHD costs €100,000.⁴⁵

The cost of GHD treatment differs substantially across the globe, so the economic burden varies from country to country.⁴⁵ Although the total cost of GHD treatment is considerable, it can be reduced by improving adherence, reducing wastage, and promoting prescriptive appropriateness.⁴⁵

The choice of elements to support treatment, such as the administration device, can affect treatment efficacy and healthcare costs.⁴⁶ In a cost–consequence analysis, daily GH administered in children using an autoinjector that allows for adherence monitoring had the lowest financial cost compared with other treatments and devices for administration.⁴⁶