The Growth Axis - Part 1 : physiology and disorders of height and growth

 Growth isn’t just about getting taller, it’s about coordinated development across tissues, organs, and systems. The hypothalamic-pituitary-somatomedin (HPS) axis governs this process, linking brain signals to liver output and peripheral tissue response. It’s a slow axis, but a powerful one - and when it fails, the consequences are lifelong.

🧠 Growth Hormone: Where It Comes From and How It’s Made

The HPS axis begins in the hypothalamus, which releases:

• GHRH (growth hormone-releasing hormone) → stimulates GH release
•  Somatostatin → inhibits GH release

Growth hormone (GH) is produced by somatotroph cells in the anterior pituitary, specifically, the pars distalis which respond to these signals. GH is released in pulses, especially during deep sleep. That’s why random GH levels are unreliable - we measure IGF-1 instead, which reflects cumulative GH activity.

There’s also a third player: ghrelin, a hormone from the stomach that rises during fasting and stimulates GH secretion. It’s part of the body’s way of linking nutritional status to growth potential.

Once released, GH travels through the bloodstream and binds to GH receptors on target tissues especially the liver. This triggers production of IGF-1 (insulin-like growth factor 1) — also known as somatomedin C. IGF-1 mediates many of GH’s growth-promoting effects, especially on bone, cartilage, and muscle.

💡GH is the upstream signal. IGF-1 is the downstream effector. If GH is normal but IGF-1 is low, the problem may be receptor-level or post-receptor.

🧬 What GH and IGF-1 Actually Do 

🧠 Growth Hormone (GH) — The Upstream Signal

GH is secreted in pulses from the anterior pituitary, especially during sleep. It acts directly on tissues and indirectly via IGF-1.

Direct effects of GH:

• Stimulates lipolysis → mobilises fat stores for energy
• Promotes gluconeogenesis → increases hepatic glucose output
• Raises blood glucose → antagonises insulin (anti-insulin effect)
• Enhances protein synthesis → supports muscle and tissue repair
• Increases bone turnover → activates osteoblasts and osteoclasts
• Stimulates IGF-1 production in the liver and other tissues

💡 GH is catabolic in fat and carbohydrate metabolism, but anabolic in protein and bone.

🧬 IGF-1 — The Downstream Effector

IGF-1 is produced primarily in the liver in response to GH. It mediates most of GH’s growth-promoting effects, especially in bone and soft tissue.

Key effects of IGF-1:

• Stimulates chondrocyte proliferation in growth plates → drives longitudinal bone growth
• Promotes hypertrophy and differentiation of muscle cells → enhances lean mass
• Supports organ growth and maturation → especially brain, heart, and kidneys
• Inhibits apoptosis → promotes cell survival in developing tissues
• Provides negative feedback to the hypothalamus and pituitary → regulates GH secretion

💡 IGF-1 is anabolic and growth-promoting — it’s the hormone that actually builds the body.

🧬 GH and Free Fatty Acids — Mobilising Energy for Growth

One of GH’s key direct effects is to stimulate lipolysis — the breakdown of triglycerides in adipose tissue. This releases free fatty acids (FFA) into the bloodstream, which serve as an energy source during fasting or growth.

Why GH promotes FFA release:

• GH is anti-insulin in fat metabolism
• It activates hormone-sensitive lipase in adipocytes
• Triglycerides are broken down into glycerol and FFA
• FFA can be used for ATP production, sparing glucose for other tissues

💡 This is especially important during overnight fasting, when GH pulses help maintain energy balance without triggering hypoglycaemia. GH  frees up energy substrates (like FFA) to support anabolic processes like protein synthesis and growth. That’s why GH excess can lead to insulin resistance, and GH deficiency may cause hypoglycaemia — especially in neonates.

While GH stimulates lipolysis, releasing FFA into the bloodstream, elevated FFA levels can inhibit further GH secretion. This is a form of metabolic feedback — the body saying, “We’ve mobilised enough energy for now.”

Mechanism:

• GH → stimulates lipolysis → ↑ FFA
• ↑ FFA → signals hypothalamus/pituitary to reduce GH pulses
• This helps prevent excessive catabolism and maintains metabolic balance

🧠 GH is pulsatile and tightly regulated. Once its metabolic goals are met (e.g. sufficient FFA for energy), feedback signals like FFA help dampen further secretion — just like IGF-1 does for growth.

🧩 Somatostatin — The Quiet Brake on Growth

Somatostatin is the inhibitory hormone in the GH axis — the counterweight to GHRH and ghrelin. It’s secreted by the hypothalamus, pancreatic delta cells, and GI tract, but in the context of growth, its key role is in the hypothalamic–pituitary feedback loop.

🧠 What It Does

• Inhibits GH release from somatotrophs in the anterior pituitary
• Suppresses TSH, insulin, glucagon, and GI hormones
• Slows gastric emptying and intestinal absorption
• Responds to rising IGF-1 levels — part of the negative feedback loop

💡 Somatostatin doesn’t just oppose GHRH — it’s activated by IGF-1 to close the loop and prevent runaway growth.

💊 Clinical Relevance

• Somatostatin analogues (e.g. octreotide, lanreotide) are used to treat:
• Acromegaly — suppress GH secretion from pituitary adenomas
• Neuroendocrine tumours — reduce hormone release
• Variceal bleeding — reduce splanchnic blood flow

🧠 Somatostatin is the brake. Without it, GH secretion would run unchecked. In acromegaly, we mimic its action pharmacologically to restore balance.

🧠 Short Stature and Delayed Development

When a child isn’t growing as expected, the HPS axis is one of several systems to consider. But it’s not just about height — it’s about growth velocity, pubertal timing, and developmental milestones.

Start by asking:

•  Is the child proportionate?
• Is growth velocity normal?
• Are other systems (thyroid, nutrition, chronic illness) involved?
•  Is puberty delayed or discordant?

📉 Growth Hormone Deficiency: When the Signal Is Missing

Growth hormone deficiency (GHD) isn’t just about being short — it’s about a failure of the body’s growth signalling system. GH is the upstream driver of growth, metabolism, and development. Without it, the liver doesn’t produce IGF-1, the growth plates slow down, and the body struggles to build tissue.

But the key question is: why is GH missing?

🧬 Why GH Might Be Deficient: Underlying Causes

GH deficiency can be congenital, acquired, or functional. Each has a different pathophysiology and clinical pattern.

1. Congenital Causes

• Pituitary hypoplasia or aplasia
• Midline defects (e.g. septo-optic dysplasia, cleft palate)
• Genetic mutations affecting GH production or receptor function
• Often present with normal birth length, but poor postnatal growth

🧠 These children may also have other pituitary hormone deficiencies — look for signs of hypothyroidism or adrenal insufficiency.

2. Acquired Causes

•  Trauma (e.g. head injury, birth asphyxia)
• Tumours (e.g. craniopharyngioma, optic glioma)
• Radiation therapy to the brain
•   Infiltrative diseases (e.g. histiocytosis, sarcoidosis)

🧠 Damage to the hypothalamus or pituitary can disrupt GH release — often alongside other hormonal deficits.

3. Functional or Secondary Causes

• Chronic illness (e.g. renal failure, inflammatory bowel disease)
• Malnutrition or psychosocial deprivation
• Hypothyroidism — thyroid hormone is permissive for GH action
• Constitutional delay — a benign variant with late but normal puberty and growth

💡 Not all short stature is pathological — but true GH deficiency has a distinct biochemical and clinical profile.

🌱 Constitutional Delay vs Pathological Short Stature — What’s the Difference?

Not all short children are unwell. Some are simply growing on their own schedule. The challenge is knowing when to worry and when to reassure.

🧠 Constitutional Delay of Growth and Puberty (CDGP)

This is a normal variant, not a disease. These children:

• Are often short for age, but have normal body proportions
• Show slow but steady growth velocity
• Have delayed bone age - but it matches their height age
• Often have a family history of “late bloomers”
• Eventually enter puberty and reach a normal adult height

💡 Their growth plates are still open, and their HPS axis is intact, just running on a slower clock.

🧠If the child is healthy, growing steadily, and has delayed puberty with delayed bone age — think CDGP.

🧬 Pathological Short Stature

This includes endocrine, genetic, nutritional, and chronic disease causes. These children:

• May have poor growth velocity — falling off percentiles
• May show disproportionate body segments (e.g. short limbs)
• Often have normal or advanced bone age relative to height
• May have systemic signs — fatigue, GI symptoms, dysmorphic features
• Require investigation for GH deficiency, hypothyroidism, coeliac disease, or skeletal dysplasia

🧠 If the child is short and not growing steadily, or has other signs of systemic illness — investigate further.

💡 Bone age is your ally — it tells you whether the child is delayed or truly deficient.

🩺 Clinical Presentation: What GH Deficiency Looks Like

Children with GH deficiency typically show:

• Slow growth velocity — falling off percentiles over time
• Delayed bone age — skeletal maturity lags behind chronological age
• Immature facial features — frontal bossing, high-pitched voice
• Normal body proportions — unlike skeletal dysplasias
• Possible hypoglycaemia — GH supports glucose production
• Possible micropenis or hypoglycaemia in neonates — if panhypopituitarism

🧠 Look at the growth velocity, not just the height. A child who’s short but growing steadily may be constitutionally small. A child who’s falling off the curve needs investigation.

🧪 Investigations: What to Order and Why

• Growth charts: track height, weight, and velocity over time
•  Bone age X-ray: assess skeletal maturity
• IGF-1 and IGFBP-3: stable markers of GH activity
• GH stimulation test: uses insulin, arginine, or clonidine to provoke GH release
• MRI brain: assess pituitary and hypothalamus
• Thyroid function tests: exclude hypothyroidism
• Coeliac screen: exclude malabsorption

💡 GH is secreted in pulses — so random levels are misleading. IGF-1 gives a more reliable picture of overall GH activity.

⚖️ GH Deficiency vs IGF-1 Deficiency — Where’s the Problem?

Once you understand the GH–IGF-1 axis, you can start asking:
Is the signal missing? Or is the response broken?

GH Deficiency

• May be congenital (e.g. pituitary hypoplasia, midline defects)
• Or acquired (e.g. trauma, tumour, radiation)
• Presents with slow growth velocity, delayed bone age, and immature facial features
• Often normal birth length, but poor postnatal growth
• May be associated with cleft palate, optic nerve hypoplasia, or other midline anomalies

IGF-1 Deficiency or Resistance

• Can mimic GH deficiency clinically
• May be due to GH receptor mutations (e.g. Laron syndrome)
• IGF-1 levels are low despite normal or high GH

🧠 If GH is high but IGF-1 is low, the problem is downstream — the liver isn’t responding, or the receptors aren’t working.

💡 Always interpret IGF-1 in context — it reflects cumulative GH activity, not just a snapshot.

 

🎬 Growth hormone deficiency - TV actor Emmanuel Lewis 

• Star: of the 1980s sitcom Webster
• Diagnosis: Growth hormone deficiency in childhood but did not have treatment
• Appearance: Retained a childlike look into adulthood due to delayed skeletal maturation and short stature
• Role: Played a 5-year-old character despite being 12 years old in real life
• At age 12 during filming: 101 cm (3'4")
• Adult height: ~130 cm (4'3")

🧠 GH deficiency causes proportionate short stature, delayed bone age, and immature facial features — all of which were evident in Lewis’s public persona.

💡 His case shows how endocrine disorders can shape not just physiology, but also identity and career — especially when they affect appearance and development.

📏 Gigantism: When GH Excess Starts Early

Gigantism occurs when excess growth hormone (GH) is present before the epiphyseal growth plates have fused, typically in childhood or adolescence. These plates, made of cartilage, are the zones where long bones elongate. They remain open until late puberty, under the influence of sex steroids

When GH is elevated during this window:

• It stimulates the liver to produce IGF-1, which acts directly on chondrocytes in the growth plates
• IGF-1 promotes proliferation and hypertrophy of these cells, leading to accelerated linear bone growth
• The result is excessive height, often with normal body proportions — unless the excess is extreme or prolonged

Clinical Presentation

• The child is unusually tall — but it’s not just height. Look at growth velocity.
• Hands, feet, and facial bones may enlarge early.
• Puberty may be delayed or discordant.
• Often caused by a pituitary adenoma secreting GH.

🧠 Ask: Is the child growing too fast for their age and bone maturity? Are other pituitary hormones affected?

Investigations

• IGF-1: elevated
• GH suppression test (e.g. oral glucose): GH fails to suppress
• MRI brain: pituitary tumour
• Bone age: may be advanced

💡 Gigantism is rare, but early recognition prevents irreversible height and skeletal distortion.

🦴 Acromegaly: Why GH Excess Doesn’t Cause Height Gain in Adults

Acromegaly occurs when GH excess begins after epiphyseal fusion — usually in adulthood. By this point, the growth plates have ossified, and longitudinal bone growth is no longer possible.

So what does GH do instead?

• It still stimulates IGF-1, but now the effects are on soft tissues, cartilage, and membranous bones
• Bones thicken rather than lengthen — especially the jaw (mandible), brow (frontal bone), and hands/feet
• Soft tissues enlarge — leading to coarse facial features, widened fingers, and organomegaly
• GH also promotes insulin resistance, sweating, and joint pain due to tissue overgrowth
• 

💡 The same hormone, acting on the same receptors, produces different outcomes depending on the developmental context. That’s the key to understanding the difference

Clinical Presentation

• The patient may notice shoe or ring size increasing
• Facial features become coarse — enlarged jaw, brow, nose
• Hands and feet widen
• Symptoms are often subtle and progress over years
• Commonly caused by a GH-secreting pituitary adenoma

🧠 Ask: Is this a slow change in appearance, not explained by weight gain or ageing? Are there systemic signs (sweating, joint pain, insulin resistance)?

Investigations

• IGF-1: elevated
• GH suppression test: fails to suppress
• MRI brain: pituitary adenoma
• Glucose tolerance test: may show impaired glucose handling

💡 Acromegaly is often missed — it’s slow, insidious, and systemic. Look for patterns across time and tissues.

🧠 Why Is There Too Much GH? The Source of the Problem

In both gigantism and acromegaly, the underlying issue is excess growth hormone — but the source is almost always the same: a pituitary adenoma.

These are benign tumours arising from somatotroph cells in the anterior pituitary — the very cells responsible for GH production. They’re usually slow-growing and monoclonal, meaning they come from a single cell that’s lost its regulatory control.

Here’s what happens:

• The tumour secretes GH autonomously, without regard for hypothalamic signals or negative feedback
• GH levels rise persistently, leading to elevated IGF-1 from the liver
• The feedback loop (GH → IGF-1 → ↓GHRH, ↑somatostatin) is intact, but overridden by the tumour’s output
• Other pituitary functions may be compressed or disrupted, depending on tumour size

🧠 This isn’t a failure of the axis — it’s a hijacking. The tumour acts like a rogue gland, producing GH independently of physiological need.

Timing Is Everything:

• If the tumour develops before epiphyseal fusion, the excess GH drives longitudinal bone growth → gigantism
• If it develops after fusion, the same GH drives bone thickening and soft tissue growth → acromegaly

💡 Same hormone, same source — different outcomes depending on skeletal maturity.

Gigantism and Acromegaly in One Patient

It’s entirely possible for a patient to show features of both gigantism and acromegaly. The key is when the GH excess begins - a fascinating illustration of the pathophysiology.

If a GH-secreting pituitary adenoma develops in late childhood or adolescence, it may first cause:

• Gigantism: accelerated height gain while the epiphyseal growth plates are still open
• Then, as puberty progresses and the plates fuse, the same tumour continues to secrete GH, leading to:
• Acromegaly: thickening of bones, enlargement of soft tissues, and metabolic changes

🧠 The same tumour, same hormone, same feedback failure — but the skeletal maturity of the patient determines whether bones grow longer or thicker.

💡 Clinically, these patients may be unusually tall and have acromegalic features. Recognising this biphasic presentation helps avoid misdiagnosis and guides appropriate imaging and endocrine workup.

💪 Acromegaly and gigantism -  WWE wrestler "The Great Khali" 

• Height: 2.15 m (7'1" )
• Weight: ~157 kg 
• Condition: Diagnosed with acromegaly, a disorder caused by excess growth hormone
• Cause: A pituitary adenoma that secreted GH continuously
• Surgical history: Had the tumour removed in 2012
• Features:
  • Enlarged jaw and forehead
  • Massive hands and feet
  • Deep voice and coarse facial features
  • Joint pain and mobility issues

🧠 Khali’s case shows the timing-dependent effects of GH excess. His growth began before epiphyseal fusion, causing gigantism, and continued into adulthood, leading to acromegalic changes.

💡 Compare this to someone with adult-onset GH excess — they won’t grow taller, but their bones and soft tissues will thicken.

🧠 Wrapping Up: Why the Growth Axis Matters

The HPS axis teaches students to think longitudinally — not just about hormone levels, but about developmental trajectories. It’s a slow axis, but a revealing one. It reminds us that growth is more than height — it’s a reflection of systemic health, endocrine coordination, and cellular response.

In the next post we will look at some more famous people with gigantism and acromegaly - including the tallest human who ever lived -  and how their endocrine clinical features are evident. 

📚 Want to learn more?

• 🧠 All endocrine system posts →
• 🧬 The HPA axis →
• 🦋 The thyroid axis →
• 💊 The adrenal axis →
• 📏 The Growth Axis – Part 1: Physiology and disorders of height and growth →
• 🎭 The Growth Axis – Part 2: Famous faces of endocrinology →