Defisiensi Growth Hormone

01Pathophysiology

Growth hormone (GH) is synthesized and secreted by somatotroph cells in the anterior pituitary gland. Its release is regulated by two hypothalamic peptides: growth hormone-releasing hormone (GHRH), which stimulates secretion, and somatostatin, which inhibits it. GH acts both directly on tissues and indirectly through insulin-like growth factor 1 (IGF-1), which is produced primarily in the liver. IGF-1 mediates most of the growth-promoting effects of GH on the skeletal growth plates by stimulating chondrocyte proliferation and hypertrophy within the epiphyseal physis.

When GH secretion is insufficient, the downstream production of IGF-1 falls. This leads to reduced linear growth velocity, which is the hallmark of the disease. Because GH deficiency affects longitudinal bone growth proportionally across all segments, the child remains proportionately short, distinguishing this condition from skeletal dysplasias where limb-to-trunk ratios are abnormal.

GH also has important metabolic functions. It promotes lipolysis and opposes insulin action. In deficiency states, loss of lipolytic drive results in increased truncal adiposity. In neonates, GH contributes to hepatic gluconeogenesis and counter-regulatory glucose homeostasis; therefore, neonatal GHD can present with recurrent hypoglycemia, sometimes severe enough to cause seizures. Additionally, GH synergizes with gonadotropins during sexual development. Male neonates with combined pituitary hormone deficiency (including GH and gonadotropins) may present with micropenis and cryptorchidism.

The "cherubic" or doll-like facies is explained by midfacial hypoplasia. GH is necessary for normal development of the facial bones, particularly the midface. Without adequate GH, the forehead appears prominent (frontal bossing), the nasal bridge is depressed, and the overall facial appearance looks immature relative to chronologic age.

In congenital forms, transcription factor mutations (PIT-1, PROP-1, HESX1, LHX3) can cause combined pituitary hormone deficiency, meaning GH deficiency may coexist with deficiencies of TSH, ACTH, gonadotropins, or prolactin. This is a high-yield concept: a child with short stature, hypothyroidism, and hypocortisolism should raise suspicion for a panhypopituitary state, not isolated thyroid or adrenal disease.

02Classification and Clinical Manifestation

Classification by Etiology

Clinical Manifestation by Age of Onset

03Diagnostic Workup

IGF-1 and IGFBP-3 serve as the best initial screening tests because they reflect integrated GH secretion over time and are not affected by the pulsatile nature of GH release. A single random GH level is useless for diagnosis because GH is secreted in pulses (primarily during deep sleep), and between pulses, GH levels are essentially undetectable even in normal individuals. This is a classic exam trap: a random GH level cannot be used to diagnose or exclude GHD.

If screening values are low, the next step is the GH stimulation test. This is the gold standard. Two pharmacologic provocative agents must be used because no single agent has perfect sensitivity. Commonly tested stimuli include insulin-induced hypoglycemia (the insulin tolerance test, considered the most reliable but carries risk of severe hypoglycemia), arginine, clonidine, glucagon, and L-DOPA. A peak GH response of less than 10 ng/mL after stimulation is the traditional cutoff that confirms deficiency. For neonates or very young infants, a random GH level may be interpretable because neonates have elevated baseline GH; a low random GH in the neonatal period can be diagnostic.

Bone age X-ray (Greulich-Pyle method, left hand and wrist) is obtained in virtually all children evaluated for short stature. In GHD, bone age is significantly delayed, typically more than 2 standard deviations behind chronologic age. This finding is supportive but not diagnostic on its own, since constitutional delay of growth and puberty also presents with delayed bone age. The key distinguishing factor is that constitutional delay has a normal growth velocity and normal IGF-1 for bone age, while GHD has a declining growth velocity and low IGF-1.

MRI of the brain with pituitary protocol is essential in all confirmed cases to identify structural causes. The classic triad suggesting congenital GHD on MRI includes anterior pituitary hypoplasia, ectopic posterior pituitary bright spot, and thin or absent pituitary stalk. If a mass lesion is identified, craniopharyngioma is the leading differential. Craniopharyngioma classically shows suprasellar calcifications on CT and a cystic-solid mass on MRI.

In all patients diagnosed with GHD, a full anterior pituitary hormone panel must be obtained to exclude combined deficiencies. This includes thyroid function (free T4, TSH), adrenal function (morning cortisol or cosyntropin stimulation test), and gonadotropins in adolescents. Failure to detect and treat concurrent central adrenal insufficiency before initiating GH therapy can precipitate an adrenal crisis because GH enhances cortisol clearance through induction of 11-beta-hydroxysteroid dehydrogenase type 1.

04Management and Treatment

Recombinant human GH (rhGH) is the cornerstone of treatment. In children, the standard dose ranges from 0.025 to 0.05 mg/kg/day, given as a single daily subcutaneous injection, preferably at bedtime to replicate the normal physiologic peak of GH during slow-wave sleep. Treatment is continued until the child has reached near-final adult height or radiographic evidence of epiphyseal closure is confirmed.

For patients with combined pituitary hormone deficiency, the sequence of hormone replacement matters and is a commonly tested concept. Glucocorticoid replacement must be initiated before levothyroxine, because thyroid hormone increases metabolic rate and cortisol clearance, which can unmask or worsen adrenal insufficiency. Similarly, GH therapy should not be started until the cortisol axis is adequately replaced, since GH increases conversion of cortisone to cortisol peripherally and can alter cortisol metabolism.

Monitoring during treatment is centered on IGF-1 levels (which should be maintained within the age-appropriate normal range; supra-physiologic IGF-1 levels increase the theoretical risk of adverse effects), growth velocity (a good first-year response is typically 10 to 12 cm/year), and periodic bone age films to track skeletal maturation. Over-treatment can accelerate bone age advancement and paradoxically reduce final adult height.

Adverse effects of GH therapy that are high-yield for exams include benign intracranial hypertension (pseudotumor cerebri), presenting with headache and papilledema shortly after initiating therapy. Slipped capital femoral epiphysis (SCFE) can occur because GH stimulates rapid growth at the proximal femoral physis; any child on GH therapy who develops hip or knee pain requires urgent evaluation. Scoliosis progression can also be exacerbated during rapid growth. GH is contraindicated in active malignancy because of its mitogenic effects through IGF-1, though evidence does not show increased de novo cancer risk with replacement doses in GHD.

Upon reaching final height, GH therapy is temporarily discontinued and the GH axis is re-tested. If stimulation testing confirms persistent GHD in adulthood, GH replacement is resumed at a lower adult dose (0.15 to 0.3 mg/day, not weight-based) for its metabolic benefits, including maintenance of lean body mass, bone mineral density, lipid profile, and cardiovascular health.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most common mistake students make with GHD questions is confusing it with constitutional delay of growth and puberty. Both conditions present with short stature and delayed bone age. The discriminating clue is growth velocity: constitutional delay maintains a normal (though slow-for-age) growth velocity tracking along a consistent percentile, while GHD shows a declining growth velocity with progressive percentile crossing. If the vignette describes a child "falling off the growth curve," think GHD. If the vignette says "always been at the 5th percentile but growing steadily," think constitutional delay or familial short stature.

Another classic trap is the random GH level. Because GH is secreted in pulses, a single random measurement is meaningless and should never be used to diagnose or exclude GHD. The exam will tempt you with a "normal random GH" as a distractor to steer you away from the diagnosis. The correct screening test is IGF-1 (which reflects average GH activity), and the confirmatory test is the GH stimulation test.

Watch for the vignette that describes a child with GHD features plus hypothyroidism and/or adrenal insufficiency. This signals combined pituitary hormone deficiency, and the next best step in management is cortisol replacement before levothyroxine, not starting GH.

A neonatal presentation of recurrent hypoglycemia, micropenis, and prolonged jaundice is a classic triad for congenital GHD or panhypopituitarism. Do not attribute neonatal hypoglycemia to "feeding difficulties" when these other features are present.

Finally, remember Laron syndrome as the ultimate distractor: the phenotype is identical to GHD, but GH levels are high (not low). This tests whether you understand the GH-IGF-1 axis. The treatment for Laron syndrome is recombinant IGF-1 (mecasermin), not GH, because the receptor is defective.

The core competency being tested in GHD questions is the ability to distinguish proportionate short stature with pathologic growth deceleration from benign growth variants, to correctly sequence screening versus confirmatory testing, and to recognize the clinical significance of combined pituitary hormone deficiencies in guiding the order of hormone replacement.