Suspected Growth Hormone Deficiency (GHD) in Children

A suspicion of growth hormone deficiency (GHD) in children typically arises when certain clinical and historical indicators are present. Common warning signs include:

  1. Growth Delay
  • The most important criterion is a significant delay in growth, such as:
    • Height < 3rd percentile (according to age norms)
    • Growth velocity < 4 cm/year during childhood
    • Drop of more than two percentile lines within a year
  1. Discrepancy from Genetic Target Height
  • If the child is significantly shorter than expected based on parental heights (target height = [father’s height + mother’s height ± 13 cm] / 2)
  1. Additional Physical Characteristics
  • Delayed bone age (e.g., X-ray of the left hand)
  • Childlike face (“doll face”), high forehead
  • Increased subcutaneous fat, especially abdominal
  • Micropenis (in boys, noticeable even in infancy)
  • Hypoglycemia during infancy
  • Delayed or absent puberty
  1. Risk Factors from Medical History
  • Prematurity, intrauterine growth retardation (SGA)
  • Birth complications (e.g., asphyxia, hypoxia)
  • Central malformations (e.g., agenesis of the septum pellucidum)
  • Cranial irradiation or tumors in the hypothalamic/pituitary region
  • Trauma or surgeries involving the central nervous system (CNS)

Diagnostic Approach

If GHD is suspected, a pediatric endocrinological evaluation follows, including:

  • Documenting height, weight, BMI, growth velocity
  • Determination of bone age
  • Measuring IGF-1 and IGFBP-3 in blood (surrogate markers for GH)
  • GH stimulation tests (e.g., insulin, arginine, or clonidine)
  • Imaging: MRI of the pituitary/hypothalamic region

Source Guidelines:

  • American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines
  • Pediatric Endocrine Society recommendations (Grimberg et al.)
  • Grimberg A & Allen DB. GH treatment and evidence-based guideline updates

Summary: Suspected GHD

  1. Medical History & Clinical Impression
    • Growth delay (e.g., < 3rd percentile)?
    • Clearly below genetic target height?
    • Other signs (e.g., hypoglycemia, micropenis)?
  2. Growth Curve & Growth Velocity
    • Growth velocity < 4 cm/year?
    • Drop across ≥ 2 percentile lines?
    • Are body proportions normal?
  3. Bone Age
    • Is bone age significantly delayed?
  4. Laboratory Diagnostics (Bloodwork)
    • Low IGF-1 and IGFBP-3?
    • Rule out other causes (e.g., thyroid dysfunction, celiac disease, chronic illnesses)?
  5. GH Stimulation Testing (e.g., Insulin, Clonidine)
    • GH response < 7–10 ng/ml → suggestive of GHD
  6. Imaging: Skull/Pituitary MRI
    • Structural anomalies in pituitary or hypothalamus?
  7. Diagnosis: Confirmed GHD
    • Start GH therapy
    • Regular follow-up (growth monitoring, IGF-1 levels, side effects)

 Bone Age Assessment Methods

  1. X-ray of Left Hand & Wrist
    • Standard method
    • Why left hand? Convention (usually non-dominant)
    • Single radiograph taken

Comparison with Reference Atlases:

  • Greulich & Pyle Atlas (GP method)
    • Most common method worldwide
    • Visual comparison of X-ray with reference images for boys/girls
    • Bone shapes, epiphyseal fusion, etc.
    • Result: bone age in years and months
  • Tanner-Whitehouse Method (TW2 or TW3)
    • Point-based system evaluating individual bones
    • More objective but time-consuming
    • Often used in research or when high precision is needed

Interpretation:

  • Bone age = chronological age → normal
  • Bone age < chronological age → e.g., GHD, constitutional delay
  • Bone age > chronological age → e.g., precocious puberty, obesity, hyperthyroidism

Typical Example:
A 10-year-old boy with a bone age of 7 years → delayed biological maturity, suggestive of endocrine or constitutional growth disorder.

Insulin Hypoglycemia Test (IHT)

Also called Insulin Tolerance Test (ITT) – a provocative function test evaluating GH and cortisol release via the hypothalamic-pituitary axis. Considered the gold standard for diagnosing GHD or ACTH deficiency.

Important Note:
This test carries risks (hypoglycemia!) and must be done in an inpatient setting with close monitoring, ideally with pediatric endocrine expertise.

Insulin Hypoglycemia Test (Children) – Procedure

  1. Preparation
  • Fasting for 8–12 hours before the test (water allowed)
  • Inform and obtain written consent
  • Place venous access
  • Prepare glucose infusion for emergencies
  1. Test Procedure
  1. Baseline values (0 min):
    • Glucose, GH, cortisol
  2. Insulin injection (i.v.):
    • Dose: 0.05–0.1 IU/kg body weight (i.v. bolus)
    • Target: Hypoglycemia ≤ 2.2 mmol/l (≤ 40 mg/dl)
  3. Monitoring every 15–30 minutes:
    • Blood draws at 15, 30, 45, 60, 90 min (GH, cortisol, glucose)
    • Hypoglycemia usually around 30 min; begin sugar checks from min 25
    • If glucose < 2.2 mmol/l → repeat GH and cortisol, then stop the test and administer glucose
    • Close clinical monitoring (consciousness, symptoms, heart rate)
  4. Stopping Criteria:
    • Severe hypoglycemia (e.g., seizure, unconsciousness)
    • Warning signs: nausea, sweating, tremors
  5. End of Test:
    • After peak hypoglycemia (60–90 min)
    • Administer oral or i.v. glucose to normalize levels
  1. Interpretation of Results

 Growth Hormone (GH)

  • Normal: GH rises to ≥ 7–10 ng/ml
  • GHD: GH < 7 ng/ml

 Cortisol

  • Normal: rise to ≥ 18–20 µg/dl (depending on lab)
  • ACTH deficiency: inadequate cortisol rise

Contraindications

  • Epilepsy
  • Coronary heart disease
  • Untreated adrenal insufficiency
  • Severe hypothyroidism
  • Very young children (prefer alternative tests)

Would you like a flowchart or schematic for this test?
In very young children (<2 years, infants), IHT is too risky due to hypoglycemia sensitivity, so alternative stimulation tests are preferred.

Alternative GH Stimulation Tests in Young Children

  1. Clonidine Test
    • Most common in small children
    • Clonidine stimulates GH via central α2-receptors
    • Dose: 0.15 mg/m² orally
    • Blood draws: 0, 30, 60, 90, 120 min (GH)
    • GH ≥ 7–10 ng/ml → normal
    •  Side effects: hypotension, sedation
  2. Arginine Test
    • Arginine suppresses somatostatin → indirect GH increase
    • Often used as a second confirmatory test
    • Dose: 0.5 g/kg i.v. over 30 min (max 30 g)
    • Blood draws: 0, 30, 60, 90 min
    • GH ≥ 7–10 ng/ml → GHD unlikely
  3. Glucagon Test
    • Less common, good alternative when others are contraindicated
    • Glucagon i.m. or s.c. (0.03–0.1 mg/kg, max 1 mg)
    • GH response often delayed (peak at 120–180 min)
    • Also allows simultaneous cortisol assessment
  4. Spontaneous Hypoglycemia in Infants
    • If spontaneous hypoglycemia occurs in the neonatal period:
      • Draw blood during the hypoglycemic episode: GH, cortisol, insulin
      • GH should be elevated during hypoglycemia
      • If not → suspicion of GHD

 Note:

For a reliable diagnosis, at least two different stimulation tests are required, unless there are clear symptoms in neonates (e.g., micropenis, hypoglycemia, MRI abnormalities).

GH Therapy in Confirmed GHD

Treatment is with recombinant human growth hormone (rhGH) – a synthetically produced hormone identical to natural GH.

Basics of Growth Hormone Therapy

Indication

  • Confirmed GHD based on two pathological stimulation tests and/or
  • Typical clinical and imaging findings (e.g., pituitary aplasia, micropenis with neonatal hypoglycemia)

 Substance

  • Recombinant human growth hormone (rhGH)
  • Trade names: e.g., Genotropin, Norditropin, Humatrope, Omnitrope, Saizen

 Therapy Administration

  1. Route of Administration
  • Daily subcutaneous (s.c.) injection, typically in the evening (as GH is physiologically secreted at night)
  • Rotate injection sites (e.g., thigh, abdomen)
  1. Dosage
  • Individualized based on body weight or body surface area, for example:

Age/Indication

Typical Dose Recommendation

Children with GHD

0.025–0.035 mg/kg/day

Turner syndrome

Up to 0.045–0.050 mg/kg/day

SGA children

0.035–0.050 mg/kg/day

Chronic kidney disease

0.045–0.050 mg/kg/day

 Regular dose adjustments are required based on weight, growth, and IGF-1 levels.

  1. Monitoring and Evaluation
  • Check growth velocity, height, and IGF-1 every 3–6 months
  • Inspect injection sites
  • Annual bone age assessment
  • Monitor thyroid function – GH can unmask latent hypothyroidism

Goals of Therapy

  • Normalize growth velocity
  • Reach genetic target height (based on parental height)
  • Improve body composition (e.g., reduce fat mass)
  • In infants: Normalize glucose tolerance and support brain development

Duration of Therapy

  • Usually until epiphyseal closure (end of linear growth)
  • If GHD persists into adulthood → possible continuation at reduced dose after re-evaluation (e.g., via repeat stimulation testing)

Side Effects (rare with correct dosing)

  • Headache (pseudotumor cerebri)
  • Joint or muscle pain
  • Hyperglycemia (rare)
  • Lipodystrophy from repeated injections at the same site
  • Hypothyroidism (requires enhanced monitoring)

GH for Short Stature Without GHD: When Is It Allowed?

Even without a confirmed GHD, GH therapy may be medically and legally permissible in certain cases – though not for idiopathic short stature (ISS) by default.

 Approved Indications for GH Therapy (also without GHD):

Diagnosis

GH Therapy Approved?

Notes

 Turner syndrome

Yes

High dose

 SGA children

Yes

If < -2.5 SD at age 4 with no catch-up growth

 Chronic kidney disease

Yes

To promote growth

 Prader-Willi syndrome

Yes

Under monitoring

 Noonan syndrome

Partially

Country-dependent

 ISS (Idiopathic Short Stature)

 Not approved in the EU

Approved in the U.S. under strict criteria (e.g., < -2.25 SD and final height < 163 cm  / < 150 cm )

If Neither GHD Nor Approved Indication Is Present:

  • In Germany and most of Europe: Not reimbursed, not approved (except possibly in clinical trials)
  • Pure height enhancement in familial short stature without a pathological cause is not recommended and is ethically/medically controversial

Ethics & Indication

GH therapy is a long-term treatment with daily injections over several years – therefore:

  • Careful indication required
  • Consider the medical benefit vs. psychological burden vs. side effects
  • Manage expectations: final height gain in ISS usually only 3–7 cm

Conclusion

If a child has:

  • Short stature
  • No confirmed GHD
  • No other approved underlying condition (e.g., Turner, SGA, etc.)

→ Then GH therapy is generally not permitted.
Exceptionally, off-label use may be considered (e.g., in a study or via private funding), but only with strict medical justification and informed consent.

If you wish, I can prepare an overview table or a parent information sheet.

This is a valid and frequently asked question – especially by parents considering GH therapy.

Is Cancer Risk Increased by GH Therapy?

Short answer:

  • In children without pre-existing conditions, and with correct indication and dosing, no clear evidence of significantly increased cancer risk exists.
  • In specific risk groups (e.g., genetic syndromes or cancer survivors), a differentiated risk assessment is required.

What Do Studies Show?

 Children with GHD:

  • Long-term studies (e.g., KIGS, NCGS, SAGhE) show no general increase in cancer risk
  • Isolated concerns in cases of very high IGF-1 levels or overdosing – now avoided

Children with Genetic Syndromes (e.g., Turner, SGA, Prader-Willi):

  • Some syndromes carry an inherent tumor risk
  • GH does not appear to increase this risk when properly dosed and monitored

Childhood Cancer Survivors (e.g., brain tumors, leukemia):

  • Higher baseline risk of second tumors – independent of GH
  • GH therapy is not contraindicated, but must be closely monitored
  • Slightly increased risk of second tumors possible (e.g., meningiomas after cranial irradiation)

Possible Biological Mechanisms

  • GH increases IGF-1, which promotes cell growth and division
  • IGF-1 is associated in vitro with cancer growth – in vivo, the relationship is complex and dose-dependent
  • Goal: Keep IGF-1 within age-appropriate normal range

Safety Through Monitoring

Regular checks during therapy:

  • IGF-1 levels (must stay within normal range)
  • Clinical monitoring (growth, side effects)
  • In high-risk patients: imaging or tumor markers, if necessary

Conclusion: Cancer Risk & GH

Situation

Cancer Risk from GH

Healthy children with GHD

No increased risk at standard dosing

Children with genetic syndromes

Baseline risk elevated, GH likely safe with monitoring

Childhood cancer survivors

Slight increased risk of second tumors; GH requires caution and close follow-up

After epiphyseal closure and completion of linear growth, it is recommended to reassess GH status:

Childhood GHD does not always persist into adulthood.

Why Re-Test After Epiphyseal Closure?

  • Approximately 30–70% of children with GHD do not have persistent growth hormone deficiency in adulthood.
  • The deficiency in childhood may be transient, e.g., due to functional disorders, idiopathic GHD, or certain syndromes.
  • Growth hormone has important functions in adulthood, including:
    • Bone metabolism
    • Fat/muscle distribution
    • Cardiovascular health
    • Quality of life / energy levels

When Is the Re-Test Performed?

  • After completion of linear growth (i.e., after the pubertal growth spurt)
  • Typically 6–12 months after stopping GH therapy
  • During this period: clinical observation without GH treatment

How Is Re-Testing Done?

  • Repeat GH stimulation test (e.g., with insulin, glucagon, or arginine)
  • Additionally: IGF-1 levels
  • Possibly also MRI, if there are unclear structural abnormalities

 GH substitution in adulthood is only indicated if GHD is confirmed to persist (at a lower dose!)

Who Does Not Require Re-Testing?

A re-test is not necessary if:

  • Congenital GHD with structural abnormalities (e.g., pituitary aplasia)
  • Multiple pituitary hormone deficiencies
  • Confirmed GHD with very low GH levels in childhood

Conclusion:

Situation

Re-Test After Growth?

Idiopathic GHD

 Yes, re-testing recommended

Structural defect / multiple hormone deficiencies

No, GHD likely persists

After cancer therapy

 Yes, if unclear

GH replacement in adulthood

Only if persistent GHD is confirmed