Growth Hormone Regulation
What are the limitations of measuring blood samples?
Any measurement technique has errors - in RIA , there are experimenter errors (e.g. pipetting errors), but also intrinsic errors due to the technique Measurements are limited by the number of samples that can be taken
Where are GHRH neurons located?
Arcuate nucleus of the hypothalamus
What are the effects of excessive GH?
Before puberty, excessive GH secretion can result in giantism - excess growth is most marked in the length of limbs and in hands and feet. After puberty, growth in the length of the long bones is not possible (once the epiphyses in the long bones have fused). Increased bone growth thereafter is confined to areas such as the hands, feet, skull, shoulder blades and chest - acromegaly. In boys, the precocious puberty usually arises from premature hyperactivation of the hypothalamus. Associated with an early growth spurt, but growth rates stop when the epiphyses fuse because of premature gonadal activation
What happens with GH deficiency?
Child with GH deficiency is often small, with an immature face and chubby body build. The rate of growth of all body parts is slow, so that the child's proportions remain normal
What stimulates GH release?
GH secreting cells are stimulated to synthesize and release GH by the intermittent arrival of growth hormone releasing hormone (GHRH) from the hypothalamus
How are GH, GHRH and somatostatin similar?
GH, GHRH and somatostatin are all peptides- stored in large, dense core vesicles, released by calcium-dependent exocytosis - act via G-protein coupled membrane receptors
What type of receptor type for GHRH?
GPCR Mechanism of the action of growth hormone-releasing hormone (GHRH) on Ca2+ and K+ channels: coupling with protein kinase A (PKA) and protein kinase C (PKC) systems.
How does ghrelin affect GH?
Ghrelin acts both on the somatotrophs to release GH directly, and within the hypothalamus to stimulate the release of GHRH. At the pituitary, ghrelin and GHRH act independently to stimulate GH release - via different receptors and different intracellular signalling pathways
How do acromegaly patients differ in their patterns of GH secretion?
Hypersecretion of GH Frequent blood sampling with serum GH measurement shows that in normal subjects (left panel) GH can fluctuate between undetectable levels (most of the time) and peaks of up to 30 μg/l (90 mIU/l), owing to the episodic nature of GH secretion. In patients with acromegaly (right panel), GH hypersecretion is continuous and GH never returns to undetectable levels.
Where is growth hormone synthesised?
Made in specialised cells of the pituitary gland (somatotrophs). It is packaged in neurosecretory vesicles and is secreted by calcium dependent exocytosis
Indirect effects of GH
Mediated primarily by insulin like growth factor 1 (IGF-1) secreted from the liver and other tissues in response to GH. Most of the growth promoting effects of GH are due to IGF-1
What subpopulations of neurons are in the arcuate nucleus?
Neurosecretory GHRH cells Neurosecretory dopamine cells (sometimes called TIDA neurons - Tuberoinfundibular Dopamine neurons) that regulate prolactin secretion POMC-containing cells that make beta-endorphin and alpha MSH Neuropeptide Y-containing neurons that project to the paraventricular nucleus and play an important role in feeding
Where are hypothalamic hormones released?
Released by exocytosis from neurosecretory endings, into portal blood vessels at the median eminence, and transported to the anterior pituitary. Act via specific membrane receptors on sub-population of anterior pituitary endocrine cells
What is the expression pattern of estrogen receptors?
Sexually dimorphic distribution of Erbeta protein in the AVPV visualised by immunohistochemistry for female and male rats
What are somatostatins effects on somatotrophs?
Somatostatin directly hyperpolarises somatotrophs, preventing GH secretion by reducing voltage-gated calcium entry, so acting as a functional antagonist to GHRH.
What are the consequences of GH deficiency?
Symptoms - Decreased energy - Social isolation - Depressed mood - Increased anxiety Clinical features - Increased body fat - Decreased muscle mass - Decreased bone density, associated with an increased risk of fracture - Impaired cardiac function - Decreased insulin sensitivity and impaired glucose tolerance
What are the underlying causes of GH pulsatility?
The pattern of GH secretion reflects cyclic activation of GHRH release and somatostatin release, and the cyclic activation of hypothalamic release reflects in part negative feedback actions of GH and IGF-1 at the hypothalamus, leading to inhibition of GHRH neurons and activation of somatostatin neurons.
How does the pulsatile secretion of GH in male rat arise?
The pulsatile secretion of GH in the male rat arises from alternating episodes of GHRH release and somatostatin release, which apparently reflect neuronal interactions between the GHRH and somatostatin cells.
What is the hypothalamic control on GH secretion?
The secretion of GH from the somatotrophs of the anterior pituitary is controlled by two hypothalamic neuroendocrine systems: the GHRH neurons and the somatostatin neurons. These stimulate and inhibit GH secretion respectively
What neurons are in the supraoptic nucleus of the hypothalamus?
The supraoptic nucleus of the hypothalamus contains only magnocellular oxytocin neurons and vasopressin neurons, all of which project to the posterior pituitary gland
What types of neurons are in the paraventricular nucleus of the hypothalamus?
1. Magnocellular oxytocin neurons that project to the posterior pituitary gland - oxytocin regulates milk let-down and parturition 2. Magnocellular vasopressin neurons that project to the posterior pituitary gland - vasopressin released from these neurons acts on the kidney to regulate antidiuresis 3. Parvocellular TRH cells that project to the median eminence- these regulate pituitary secretion of TSH and thence thyroid activity 4. Parvocellular CRF/vasopressin cells that project to the median eminence - these regulate ACTH secretion and thence adrenal glucocorticoid secretion In addition, the paraventricular nucleus contains populations of centrally projecting neurons including populations of oxytocin neurons, vasopressin neurons and CRF neurons that are thought to mediate behavioural and other central actions of these peptides.
What are the main features of GH secretion?
1. Pulsatile In humans, typically one pulse every 3 hours with largest pulses at night 2. Sexually dimorphic Much less marked in humans than most animals In females - lower peaks, higher trough values, more pulses In males - large peaks separated by very lower levels of secretion
What other three hormones regulate growth?
1. Thyroid stimulating hormone (TSH) - causes thyroid gland to produce thyroid hormone which regulates body metabolism and is essential for normal growth 2. Adrenocorticotropic hormone (ACTH) - causes the adrenal glands to produce cortisol (stress hormone) and other hormones that enable the body to respond to stress. Too much cortisol will cause growth failure in a child 3. Luteinising hormone (LH) and Follicle stimulating hormone (FSH) - causes the sex glands (ovaries or testes) to produce sex hormones, which are necessary for adolescent sexual development and the growth spurt that accompanies puberty
How can GH levels be measured?
Classically, to perform a radioimmunoassay, a known quantity of an antigen is made radioactive, frequently by labeling it with gamma-radioactive isotopes of iodine, such as 125-I, attached to tyrosine. This radiolabeled antigen is then mixed with a known amount of antibody for that antigen, and as a result, the two specifically bind to one another. Then, a sample of serum from a patient containing an unknown quantity of that same antigen is added. This causes the unlabeled (or "cold") antigen from the serum to compete with the radiolabeled antigen ("hot") for antibody binding sites. As the concentration of "cold" antigen is increased, more of it binds to the antibody, displacing the radiolabeled variant, and reducing the ratio of antibody-bound radiolabeled antigen to free radiolabeled antigen. The bound antigens are then separated from the unbound ones, and the radioactivity of the free(unbound) antigen remaining in the supernatant is measured using a gamma counter
What causes pituitary dwarfism?
Deficiency of GH or of GHRH (growth hormone releasing hormone) or insensitivity of GH or GHRH receptors (before puberty) results in pituitary dwarfism
How does GH secretion change during life?
Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age. GH deficiency in elderly humans has many consequences, including skeletal fragility, and increased adiposity (body fat).
What effect does exercise have on GH?
Exercise is a potent stimulator of GH secretion in most species and has been studied extensively in man. The magnitude of the GH response depends upon several factors including: - Intensity and duration of acute exercise - The muscle mass used during exercise - Degree of training Exercise and diet have a major physiological influence upon the hypothalamic regulation of GH secretion, but the pathways involved in these influences are poorly understood
Direct effects of GH
Fat cells (adipocytes): GH stimulates them to break down triglyceride and suppresses their ability to take up circulating lipids. Functions as part of energy homeostasis
What is the effect of food deprivation on GH secretion?
Food deprivation induces a dramatic alteration in GH secretion in all species studied. In rats, food deprivation inhibits pulsatile GH secretion, and refeeding results initially in low-amplitude pulses (at a higher frequency than the endogenous rhythm) giving way to normal 3h high-amplitude pulses within 6-8h.
How does GH release differ between males and females?
In both males and females, GH is normally released in pulses. However in most mammalian species this pulsatility is more marked in males than in females, and this is particularly true in the rat. Male rats (left) have a pattern of GH secretion very like that of humans, with large pulses of release typically every 3 hours or so. In female rats, (right of the graph) pulses are smaller and more frequent, but are superimposed upon a much higher basal secretion. This sexual dimorphism of GH secretion is the main explanation for the different growth rates of male and female rats. The sexual dimorphism reflects the expression of oestrogen receptors in somatostatin neurons.
Generally, what is the pattern of GH secretion?
In humans and most mammals, GH secretion is markedly pulsatile. The pattern of secretion in human is particularly similar to that in the male rat - accordingly the origin of much of our basic understanding
When is growth hormone mainly secreted?
In normal individuals, growth hormone is secreted mainly during sleep
How do neurosecretory neurons differ from typical NT releasing neurons?
Neurosecretory neurons are in many ways no different from other neurons - except that they may make exceptionally large amounts of their secretory product, and instead of releasing these products at synapses, they secrete their products into the blood. To secrete their products into blood, their nerve terminals must be on the blood side of the blood-brain barrier. In general, this barrier protects the brain from direct exposure to the blood. However there is no blood-brain barrier in the posterior pituitary, or at the external zone of the median eminence.
How is GH deficiency tested?
One way of testing for GH deficiency is to give the child a substance that stimulates GH release in normal children, and measure the amount of GH present in several blood samples obtained over a period of time. However, as any child might not respond to any given test on a given day, repeated tests might be needed to evaluate the child's ability to produce GH
GHRH
Peptide synthesised by neurons in the arcuate nucleus of the hypothalamus, and released from neurosecretory terminals at the median eminence. Promotes GH release
Somatostatin
Peptide synthesised by neurosecretory neurons of the periventricular nucleus. Inhibits GH release
Where are the somatostatin cell located?
Periventricular nucleus
What happens following prolonged infusion of somatostatin?
Prolonged infusion of somatostatin leads to a sustained inhibition of GH release, followed by a dramatic rebound secretion of GH after the end of somatostatin infusion, apparently arising from a rebound secretion of GRF. Similar rebound secretion of GHRH follows electrical stimulation of the periventricular nucleus which appears to provide a direct inhibitory projection to putative GHRH neurons in the arcuate nucleus Thus the GHRH neurons and somatostatin neurons appear to interconnect at the level of the hypothalamus within a neuronal pulse-generator network.
Physiological effects of GH in adults
Promotes muscle development and bone maintenance
Physiological effects of GH in juveniles
Promotes skeletal growth. Regulates somatic growth and to its deficiency in senescence can be attributed many greater and lesser ills