Growth Hormone & Pituitary Function

Hypothalamus-Pituitary Target Organ Axes: Feedback Control

• Learning Outcomes: Describe the role of various hormones (Growth Hormone, Prolactin, Oxytocin, ADH/Vasopressin) in the body and how defects in their levels can cause disease.

Anterior Pituitary Hormones

• General Clinical Conditions: Specific hypo- and hyper-secretory disorders exist for most anterior pituitary hormones.
• Causes: These conditions stem from either:
  • Primary: Hypo or hypersecretion of the anterior pituitary cells.
  • Secondary: Hypo or hypersecretion of hypophysiotropic hormones.

Growth Hormone (Somatotropin)

• Structure: Single chain – 191 amino acids.
• Role in Growth: Essential for growth, but not solely responsible for the final growth rate.
• Factors affecting growth rate:
  • Genetics
  • Adequate diet
  • Absence of chronic disease/stress
  • Normal levels of growth-influencing hormones
• Secretion: Pulsatile, serum concentration varies. Amplitude and frequency are influenced by age, gender, nutrition, sleep, body composition, stress, and exercise. Random serum measurement can be misleading.
• Concentration in Body: Average plasma concentration of growth hormone (GH) declines with age. (5-20 years: 6 ng/ml, 20-40 years: 3 ng/ml, 40-70 years: 1.6 ng/ml).
• Somatomedins (IGFs): GH does not act directly on target cells; instead, it stimulates somatomedins (especially IGF-1).
  • IGF-1 is the most important somatomedin
  • Primary source of circulating IGF-1 is the liver. GH stimulates IGF-1 release
  • Produced by other tissues too.
• Role in Bone Growth: GH increases skeletal frame growth in thickness and length, acting directly and indirectly on long bone epiphyseal plates via IGF-1 synthesis. Increases protein deposition in chondrocytic and osteogenic cells; stimulates differentiation of chondrocytes.
• Metabolic Actions: Promotes lipolysis and lipid oxidation; increases fatty acids in the blood. Stimulates protein synthesis in cells, particularly muscles; and conserves glucose for the brain. Antagonizes/opposes insulin action, raising blood glucose (i.e., diabetogenic effects). Promotes phosphate, water, and sodium retention when body energy needs exceed available glucose stores (e.g., fasting).
• Overall Functions: Maintains adult cardiac function and glucose homeostasis. Supports bone mineralization, adipose balance, and muscle anabolism.

Growth Hormone (GH) Deficiency

• Causes: Hypothalamic dysfunction (e.g. lack of GHRH); Pituitary defect (e.g., defect in GH production by somatotrophs); or Target cells for GH fail to respond normally.
• Symptoms (children): Dwarfism (short stature), poorly developed muscles, excess subcutaneous fat.
• Symptoms (adults): Reduced skeletal mass and strength; increased % body fat; decreased bone density; increased heart failure risk.
• Diagnosis:
  • Measure IGF-1 first.
  • If low IGF-1, use provocative testing (insulin-induced hypoglycemia) to confirm.
• Treatment: Recombinant forms of human GH.

Growth Hormone Excess

• Causes: Tumor of GH-producing anterior pituitary cells.
• Symptoms (children): Gigantism (rapid height increase) with normal body proportions.
  • Hyperglycaemia; cardiac hypertrophy; susceptibility to infection; rarely live past 20s.
• Symptoms (adults): Acromegaly.
  • Jaw and cheekbones become more prominent with thickened skin; hands and feet enlarge; peripheral nerve issues (nerve compression); frontal bossing; prognathism.
• Diagnosis: Measure IGF-1. If equivocal, use OGTT for confirmation.
• Treatment: Surgery to remove the tumor. Medical therapy with somatostatin analogs or GH receptor antagonists if tumor removal isn't possible.

Prolactin (PRL)

• Structure: 199-amino acid single chain protein.
• Secretion: Primary role in stimulating milk production. Lactotropes (PRL-producing cells) differ from other endocrine cells in the anterior pituitary primarily because they aren't part of an endocrine axis and secretion is tonically inhibited by dopamine from the hypothalamus. 
• Regulation: Tonically inhibited by dopamine. Stimulated by prolactin-releasing factors (PRFs) under conditions like suckling, stress, estrogen, and sleep, as well as dopamine antagonists (e.g., antipsychotics).
• Effects:
  • Women: Stimulates by elevated estrogens (pregnancy), inhibits GnRH synthesis during pregnancy (inhibits ovulation). Increases steadily during pregnancy; stimulates breast development; milk production. 
  • Men: Not part of male reproductive axis; inhibits GnRH, which reduces spermatogenesis.
• Biological Effects:
  • Before/after puberty: Stimulates proliferation and branching of ducts in the female breast.
  • Pregnancy: Causes development of mammary lobules and alveoli for milk production. 
  • After parturition: Stimulates milk synthesis and secretion (let-down reflex).
  • Reproduction: Excess PRL blocks synthesis and release of GnRH, preventing ovulation in women and normal sperm production in men.

Prolactin Deficiency/Excess

• Causes (Deficiency): Isolated deficiency is rare. Most have panhypopituitarism (other pituitary hormone deficiencies).
• Causes (Excess): Physiological (pregnancy/breastfeeding/stress); Pathological (pituitary adenoma or drugs that block dopamine).
• Symptoms (Deficiency): Decreased lactation.
• Symptoms (Excess):
  • Women: galactorrhea, amenorrhea, infertility.
  • Men: decreased libido and fertility.

Posterior Pituitary Hormones: ADH/Vasopressin

• Structure: Arginine Vasopressin (AVP), a peptide hormone. 
• Locations: Primarily formed in supraoptic nuclei of the hypothalamus.
• Roles: Regulates urinary water loss, extracellular fluid (ECF), and osmolarity.
• Effects: Two major effects:
  • Antidiuretic effect: Enhances water retention by the kidneys affecting distal and collecting tubules to decrease urinary output.
  • Pressor effect: Causes contraction of arteriolar smooth muscle increasing blood pressure.
• Regulation: Release depends on hypothalamic osmoreceptors and systemic baroreceptors. ADH (vasopressin) secretion is primarily regulated by osmotic and volume stimuli. Secretion stimulated by plasma hyperosmolality, plasma hypovolemia, and angiotensin II. Secretion inhibited by plasma hypoosmolality and plasma hypervolemia.
• Deficiency: Diabetes insipidus. Characterized by excessive urination (polyuria), thirst (polydipsia), and nocturia (frequent urination at night). Causes can be hypothalamic (tumors, autoimmune disease, head trauma) or nephrogenic (kidney disease, mutations in vasopressin receptor, medications such as lithium). Treatment is often exogenous ADH administration.
• **Oversecretion:**SIADH (Inappropriate ADH secretion). Increased serum ADH release from non-hypothalamic sites (e.g., lung cancer). Characterized by hyponatremia; resulting in water retention. Excess fluid, resulting in decreased serum sodium concentrations causing brain swelling and related symptoms.
  • Hyponatremia is the primary effect, due to increased water retention.

Oxytocin

• Role: Stimulates uterine contraction; triggers labor as baby moves towards birth canal through positive feedback loop. Promotes milk ejection (let-down reflex) from mammary glands. Important for social interactions in humans.
• No deficiency/excess diseases

Other Important Notes

• Lactrotroph adenoma: Commonest pituitary tumor/cause of female infertility. Medical therapy with dopamine agonists; surgery may be required if medication doesn't work.
• Important Considerations: Normal Growth also requires adequate thyroid hormone, insulin, and sex steroids.

The quiz assesses understanding of growth hormone regulation, deficiencies, and consequences of hypersecretion. It explores pituitary adenomas, hormonal imbalances, and the impact of hypophysiotropic hormones. Somatostatin's effects on hormonal changes are also examined.