Overview

• Growth hormone, aka, somatotropin, (somatotrophin) is secreted by anterior pituitary cells called somatotrophs.
• Somatotrophs make up more than half of the anterior pituitary, and growth hormone is the most abundantly secreted anterior pituitary hormone.
• Growth hormone is responsible for growth of almost all tissues, whether directly or indirectly via insulin-like growth factor 1 (IGF-1).
• Growth hormone secretion is pulsatile, and is highest during sleep.
• Growth hormone levels vary throughout life; they begin to fall after adolescence.
• Negative feedback loops regulate growth hormone secretion.

Growth Hormone Physiology

• First, we draw the hypothalamus and pituitary gland.
• Neurosecretory cells originate in the arcuate nucleus of the hypothalamus, and their axons terminate on capillaries of the hypothalamic-pituitary portal system.
• Within the anterior pituitary, there are various collections of endocrine cells;
  – We label the somatotrophs with an S, and show the nearby capillaries that deliver hormone products to the blood supply.

Growth Hormone Release

• The hypothalamus secretes growth hormone releasing hormone (GHRH) into the neurosecretory cells.
• When it reaches the anterior pituitary, GHRH stimulates somatotropin release of Growth Hormone (GH), which then travels in the blood to tissues throughout the body.

Growth Hormone Effects

• Growth effects: it increases cell growth, proliferation, and differentiation throughout the body.
• Direct effects on growth:
  – Increases bone length and muscle mass (growth hormone promotes protein deposition).
• Indirect effects on growth:
  – Diabetogenic effects: growth hormone increases glycogen breakdown in the liver to increase blood glucose, which can be used as fuel by growing body tissues.
  – Growth hormone also increases insulin-like growth factor 1release from the liver, which in turn promotes growth and differentiation of various tissues.

Be aware that IGF-1 is sometimes referred to as somatomedin-C

– Glucose-sparing effects: it increases lipolysis, and decreases glucose uptake by skeletal muscle and adipose tissue, which frees up energy for growth of tissues.

Growth Hormone Regulation

• Key regulators:
  – At the hypothalamus:
  Sleep, hypoglycemia, and stress trigger the release of growth hormone releasing hormone.
  Age and obesity are associated with reduced GHRH release, and, via negative feedback loops, glucose, IGF-1, and growth hormone also reduce GHRH release.
  – At the level of the anterior pituitary:
  Release of growth hormone is inhibited by growth hormone inhibitory hormone (aka, somatostatin, which is released by the hypothalamus), and via negative feedback signals from IGF-1 and Growth hormone (notice that IGF-1 and growth hormone provide negative feedback at both the hypothalamus and the anterior pituitary).

• Additional factors that promote and inhibit growth hormone secretion:
  – Stimulates Secretion:
  Growth hormone releasing hormone
  Decreased blood glucose
  Decreased blood free fatty acids
  Increased blood arginine (an amino acid)
  Protein deficiency and starvation
  Stress and excitement (including a variety of experiences, including exercise and trauma)
  Testosterone and estrogen
  Deep sleep
  Ghrelin, which is a growth hormone secretagogue (GHS) that is produced mainly in the stomach.

– Inhibits Secretion:
Growth hormone inhibiting hormone (aka, somatostatin)
Increased blood glucose
Increased free fatty acids
Exogenous growth hormone
Insulin-like growth factor 1 (via negative feedback)
Aging
Obesity

Pause to recognize that low blood glucose, low levels of free fatty acids, and increased levels of amino acids in the blood stimulate growth hormone release, which ultimately reverses each of these states to maintain homeostasis.

Growth Hormone Pathologies

Growth Hormone Defects

Growth hormone deficiency

• Characterized by low levels of growth hormone and IGF-1
  – If there is not enough growth hormone to trigger its production, IGF-1 will necessarily be low.
• Isolated growth hormone deficiency is often due to defects in the GH1 gene, which is responsible for growth hormone production.
• In other cases, growth hormone deficiency is an aspect of general hypopituitarism, in which other anterior pituitary hormones are also low.
• Patients can be treated with recombinant human growth hormone.
  Growth hormone insensitivity is characterized by normal or high levels of growth hormone, and low levels of IGF-1.
• This is the result of growth hormone receptor defects
  – May be hereditary, as in Laron Syndrome.
  – May acquired as a result of malnutrition, liver disease, diabetes, growth hormone receptor antibodies, or other pathologies.
• Patients can be treated with recombinant IGF-1.
• In Children:
  – Linear growth is slow (sometimes called pituitary dwarfism).
• Children often have delayed puberty, with small gonads and genitalia (micropenis).
• In Adults:
  – Body composition changes, including reduced muscle and bone mass, and increased fat mass.
  – Increased risk of cardiovascular disease (including left ventricular dysfunction and hypertension), and are more likely to develop insulin resistance.
  – Additionally, reduced exercise capacity, lethargy, and depression contribute to a lower quality of life in these patients.

Growth Hormone Excess

• Excessive section of growth hormone leads to elevated growth hormone and IGF-1
  – Be aware that prolactin is also often elevated.
• In both children and adults, the most common cause of growth hormone hypersecretion is an adenoma in the anterior pituitary.
  – Treatment often requires tumor removal.
• In Children: Gigantism
  – Growth hormone hypersecretion occurs prior to fusion of the epiphyseal plates.
  – This causes accelerated linear growth, and children are taller than their age/sex-matched peers; delayed puberty is also likely.
• In Adults: Acromegaly
  – Growth hormone hypersecretion occurs after epiphyseal plate fusion.
  – Thus, linear growth can’t occur, but bone deformation, soft tissue swelling, and enlargement of facial features, hands, and feet are common.
  – Patients are more likely to experience sleep apnea, diabetes, cardiovascular disease, arthropathy, carpal tunnel, headaches and visual disturbances due to tissue swelling and metabolic changes.