Hormonal Regulation of Growth

1. Hormonal Regulation of Growth

2. Hormonal Actions • Definition • Chemical messengers secreted by various tissues, not necessarily secreted by ductless glands. • Hormones act in an endocrine manner when secreted by cells and then transmitted via the bloodstream to act on distant target cells

3. Types of action • Neurocrine • Hormone is synthesized in a cell body of a neuron and stored in axons such as neurotransmmitters, but secreted into the bloodstream to act on distant target cells • A key regulator of animal growth and development by the hypothalamic-pituitary-peripheral gland axes

4. Types of action (cont.) • Local conveyance – site action • Paracrine- when a hormone from one cell is conveyed to an adjacent cell of different type over a short distance via interstitual fluid • Autocrine – where a hormone from one cell acts on itself or a neighboring cell of the same type • Intracrine – acts intracellularly and does not require secretion to alter the process

5. Types of action (cont.) • Tissue specificity • Allows hormones to act on target tissues without affecting other tissues or organs • Receptors – has an affinity for specific hormones that may be located at the cell • Hormones will bind and act through various enzyme systems, ion transport or gene regulation • Negative feedback loops may also regulate hormonal function

6. Chemical Nature of Hormones • Classification • Peptides/amino acid derivatives • Water soluble • Ex. Thyroxine, LH, FSH • Steroid/cholesterol derivatives • Ex. Estrogen, testosterone, progesterone • Fat soluble

7. Hypothalamic-Pituitary-Peripheral Gland Axis • Hypothalamus – the central organ of the neuroendrocrine system • Secretions from the Hypoth. Regulate the secretions from the pituitary • Located at the base of the brain • Two sections: adenohypophysis and neurohypophysis

8. Pituitary • Adenohypophysis • Pars tuberalis, pars intermedia, and pars distalis (anterior = distalis) • Neurohypophysis – • Pars nervosa and pars eminens (posterior= nervosa and intermedia) • Consists of axons whose cell bodies are in the hypothalamus

9. Posterior lobe • Antidiuretic hormone (ADH) and oxytocin are both synthesized in the hypothalamus but are stored in the posterior pituitary • ADH regulates water balance and oxytocin regulates smooth muscle contractions in mammary and uterine tissues • Intermediate lobe is responsible for MSH (melanocyte-stimulating hormone)

10. Anterior lobe • Certain hormones are secreted as tropic hormones that act on endocrine glands and are synthesized in the hypothalamus neuron cell bodies and stored in nerve terminals (synaptosomes) • Synaptosomes release hormones into the hypothalamic-hypophyseal portal system for transport to the anterior pituitary • GHRH (growth hormone releasing hormone) stimulates synthesis of GH (somatotropin) whereby somatostatin inhibits synthesis of somatotropin

11. Anterior Pituitary cont. • GnRH (gonadotropin-releasing hormone) induces gonadotrophs to produce FSH and LH – these act on gonads • Corticotropin-releasing hormone (CRH) produces adrenocorticotropic hormone (ACTH) – acts on adrenal gland • Thyroponin-releasing hormone (TRH) produces TSH (Thyroid Stimulating Hormone) – act on thyroid glandProlactin is synthesized by lactotrophs - Acts on mammary and gonads

12. Anterior Pituitary cont. • The tropin hormones are synthesized by the anterior pituitary hormones to target organs • Typical target organs are: thyroid, pancreas, adrenal glands, gonads, etc.

13. Androgens • Two types: testicular and adrenal • Testicular hormones are testosterone and androstenone • Testosterone is produced in the Leydig cells of the testes. • Androstenone is a pheromone • Known to contribute to the boar taint odor in pork

14. Androgens • Androstenone is stored in the salivary gland and accumulates in fat depots • Adrenal androgens are 17 keto steroids and are synthesized by in the cortex of the adrenal gland • Growth effects are seen by the influence of testosterone of bone and muscle. This is seen by the increasing deposition of bone salts. Thus, increased bone mass is seen more in males

15. Androgens • Muscle development is seen through androgen secretions in three ways • In utero, declines after birth, and increases at puberty • Prenatal androgens affects myogenesis • Castrated males have lower circulating GH than intact males • Androgens increase both protein synthesis and degradation, yet synthesis is stimulated greater so we see an increase in protein accretion

16. Androgens • Androgens synthesis induces the development of mature male characteristics such as: larger muscles in the forequarter, neck and crest region. • Castration diverts energy from growth of muscle development to fat deposition • Castration helps improve quality by less muscle and more fat development at an earlier age

17. Estrogens • General classification for three hormones: Estrone, Estriol, Beta-estradiol • Responsible for: growth, maturation of repro tract, female behavior, mammary development • Impact: bone, fat, and muscle tissue growth • Females have shorter skeletons due to: earlier epiphyseal closure that is a result of chondrocyte proliferation and a function of bone formation

18. Estrogens • Facilitates fat deposition • Anabolic for ruminants • Effective in castrate males for growth, yet is less effective in non-ruminants • Have little effect on intact males • In steers, estrogens increases muscle protein • Table 10.1

19. Progestins • Classified as steroid hormones • Progesterone is a member of the progestin family which is responsible for maintenance of preg. And mammary growth and devlepment • MGA is a synthetic progestin that is 100X more potent than progesterone • Improves F:G ratios in heifers and suppresses estrus

20. Synthetic Hormones • Anabolic steroids – those that result in increased tissue accretion • Androgens – improve growth, FE, carcass protein esp. in heifers • Testosterone is anabolic • Combined with estrogens, testosterone is more effective for growth parameters

21. Synthetic Hormones • TBA – Trenbolone Acetate – a synthetic steroid is weak, yet when combined with estrogen it is real effective in steers • It binds to testosterone and estrogen receptors in skeletal muscle. • This yields a slight decrease in protein synthesis and a significant result in (decrease) in protein degradation, thus an increase in protein accretion

22. Growth Hormone • GH or Somatotrophin (ST) • Produced by the anterior pituitary • Acts in an endocrine manner • Liver can synthesize growth factors to help regulate growth, acts as a mediator • GH stimulates the production of IGF-I Insulin-like growth factor-1; also called somatomedin

23. Growth Hormone • High concentrations of IGF-I inhibits GHRH and GH, thus reduces production of IGF-I • If IGF-I is too low then GHRH & GH are not inhibited so they produce IGF-I • Somatostatin is produced by the hypothalamus and delta cells of the pancreas that decreases GH secretion thus decreases IGF-I production • Table 10.5 Summary of GH Effects

24. Growth Hormone • GH affects bone by using IGF-I to increase chondrocyte proliferation and osteoblast activity. • GH increases lean growth by increasing rates of muscle protein synthesis and decreasing protein degradation • Increases in RNA & DNA accompany increased protein accretion

25. Growth Hormone • IGF-I actions on muscle include increased uptake of glucose and amino acids • IGFBP (IGF binding proteins) help transport IGF-I to target tissue like muscle • GH also increases lipolysis of fatty acids from adipocytes

26. Growth Hormone • GH is a protein hormone • Therefore, it is not a orally active hormone and admin. Via injection • GH has been shown to increase wt. gain, feed conversion while decreasing feed intake • When nutrients are limited, GH increases lipolysis, and decreases growth because IGF-I becomes uncoupled from GH, therefore IGF-I decreases. These changes causes a transfer of calories from adipose to vital functions

27. IGF’s • Are peptides that are structurally similar to proinsulin and exhibit some affinity for insulin receptors • Insulin, at high conc., will bind to IGF receptors. • IGF’s are secreted by the liver and by some other tissues in response to GH but they are not stored in the liver

28. Insulin and Glucagon • Islets of Langerhans within the pancreas contains four types of cells • Alpha cells that synthesize glucagon • Beta cells that synthesize insulin • Delta cells that synthesize somatostatin • ???? That synthesizes a pancreactic polypeptide

29. Insulin • At high conc. can stimulate general body growth through low-affinity binding to IGF receptors • Even though there may a deficiency of insulin receptors, the number of IGF receptors are normal • High circulating levels of insulin cause overgrowth of extremities and enlargement of the kidney and adrenal glands by cross reacting with IGF receptors

30. Action of Insulin • The actions of insulin on the global human metabolism level include: • Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about ⅔ of body cells). • Increase of DNA replication and protein synthesis via control of amino acid uptake. • Modification of the activity of numerous enzymes (allosteric effect).

31. The actions of insulin on cells • glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin which is directly useful in reducing high blood glucose levels as in diabetes. • Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids which are converted to triglycerides; lack of insulin causes the reverse. • Increased esterification of fatty acids – forces adipose tissue to make fats (ie, triglycerides) from fatty acid esters; lack of insulin causes the reverse.

32. The actions of insulin on cells • Decreased proteinolysis – forces reduction of protein degradation; lack of insulin increases protein degradation. • Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse. • Decreased gluconeogenesis – decreases production of glucose from various substrates in liver; lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.

33. The actions of insulin on cells • Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption. • Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. • Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract.

34. Insulin cont. • There are two types of mutually antagonistic metabolic hormones affecting blood glucose levels: • catabolic hormones (such as glucagon, growth hormone, and catecholamines), which increase blood glucose • and one anabolic hormone (insulin), which decreases blood glucose

35. Insulin cont. • Mechanisms which restore satisfactory blood glucose levels after hypoglycemia must be quick, and effective, because of the immediate serious consequences of insufficient glucose (in the extreme, coma, less immediately dangerously, confusion or unsteadiness, amongst many other effects). This is because, at least in the short term, it is far more dangerous to have too little glucose in the blood than too much.

36. Somatostatin • Somatostatin is classified as an inhibitory hormone, whose main actions are to: • Inhibit the release of growth hormone (GH) • Inhibit the release of thyroid-stimulating hormone (TSH)

37. Somatostatin • Suppress the release of gastrointestinal hormones • Gastrin • Cholecystokinin (CCK) • Secretin • Motilin • Vasoactive intestinal peptide (VIP) • Gastric inhibitory polypeptide (GIP) • Enteroglucagon (GIP)

38. Somatostatin • Lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine. • Suppress the release of pancreatic hormones • Inhibit the release of insulin • Inhibit the release of glucagon • Suppress the exocrine secretory action of pancreas. • Somatostatin opposes the effects of Growth Hormone-Releasing Hormone (GHRH)

39. Insulin and Glucagon • Glucagon and Insulin act on a negative feedback system • When one goes up the other goes down • Functions to mobilize glucose, fatty acids, and increase amino acid catabolism • Insulin dominates the system in mammals

40. Leptin • Has been found to regulate body energy storage • It is a peptide produced by adipose tissue • Appears to be important in providing signals to the hypothalamus • Ex. An increase in adipose tissue mass will induce production of leptin and in return will target the hypoth. to decrease food intake, increase energy expenditure and modulate other hormones such as insulin, GH, cortisol, etc., thus ultimately reducing adipose tissue mass

41. Glucocorticoids • Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisolreceptor and trigger similar effects. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by the specific receptors, target cells, and effects. Technically, the term corticosteroid refers to both glucocorticoids and mineralocorticoids, but is often used as a synonym for glucocorticoid.

42. Cortisol • Cortisol is a corticosteroidhormone produced by the adrenal cortex that is involved in the response to stress; it increases blood pressure, blood sugar levels, may cause infertility in women, and suppresses the immune system. Synthetic cortisol, also known as hydrocortisone, is used as a drug mainly to fight allergies and inflammation.

43. Glucocorticoids • Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life and regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Glucocorticoid receptors are found in the cells of almost all vertebrate tissues.

44. Glucocorticoids • Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the synthesis of glucose from non-hexose substrates such as amino acids and lipids and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best known metabolic function of glucocorticoids.

45. Glucocorticoids • Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis. • Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose. • Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.

46. Glucocorticoids • Glucocorticoids bind to the cytosolic glucocorticoid receptor. This type of receptor gets activated upon ligand binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The opposite mechanism is called transrepression.

47. Glucocorticoids • The activated hormone receptor interacts with specific transcription factors and prevents the transcription of targeted genes. Glucocorticoids are able to prevent the transcription of any of immune genes, including the IL-2 gene.

48. Glucocorticoids • Generally exhibit catabolic effects • Decreases muscle protein synthesis • Increases muscle protein degradation • Makes amino acids more available for glucose production and increases lipolysis by enhancing GH and catecholamine-stimulated lipolysis

49. Catecholamines • Catecholamines, adrenalin, norepinephrine are all stored in the adrenal medulla and is released when stimulated by nerve fibers • Acts on responses to stress • Adrenalin (epinephrine) acts thru the beta adrenergic receptors whereas norepinephrine act on the alpha & beta adrenergic receptors

50. Catecholamines • Effects of epinephrine include mobilization of glycogen for energy, increased blood flow, respiration, and body temp. • Epinephrine induces muscle anabolic glycolysis to meet energy needs for muscle contraction • Stress induced situations lead to DFD and PSE due to metabolic changes that create a final pH alteration • Long term stress leads to DFD while short term or acute stress leads to PSE