Endocrine Control of Growth

1. Endocrine Control of Growth

2. Endocrine glands

3. Pituitary • Anterior pituitary - oral ectoderm. • Posterior pituitary - neuroectoderm. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called the hypothalamic-hypophysial portal system The anterior pituitary synthesizes and secretes: • Growth hormone ('HGH' or 'GH' or somatotropin), released under influence of hypothalamic Growth Hormone-Releasing Factor (GHRF), inhibited by hypothalamic somatostatin • Thyroid-stimulating hormone (TSH), released under influence of hypothalamic Thyrotropin-releasing Factor (TRF); inhibited by somatostatin

4. Pituitary • Adrenocorticotropic hormone (ACTH), released under influence of hypothalamic Corticotropin-Releasing Factor (CRF) • Gonadotropins • Luteinizing hormone (also referred to as 'Lutropin' or 'LH'). • Follicle-stimulating hormone (FSH), both released under influence of Gonadotropin-Releasing Hormone (GnRH)

5. Original Somatomedin Hypothesis

6. Insulin-like Growth Factor System • 3 ligands • IGF-1 = Somatomedin-C • IGF-2 • Insulin • 6 binding proteins • IGFBP-1 to -6 • Cell surface receptors that mediate the ligand action

7. Growth Hormone • Pulsatile secretion from anterior pituitary; maximum during early stages of deep sleep • Increases DNA synthesis and cell multiplication • Adequate levels of thyroid hormone required:"permissive"

8. HGH Adipose Tissue ↓Glucose Uptake ↑Lipolysis ↓Adiposity Liver ↑RNA Synthesis ↑Protein Synthesis ↑Gluconeogenesis ↑IGF-1 Muscle ↓Glucose Uptake ↑Amino Acid Uptake ↑Protein Synthesis ↑Lean Body Mass IGF-1 Local production Bone, Heart, Lungs etc ↑Amino Acid Uptake ↑Protein Synthesis ↑RNA Synthesis ↑DNA Synthesis Organ Size Organ Function Chondrocytes ↑Amino Acid Uptake ↑Protein Synthesis ↑RNA Synthesis ↑DNA Synthesis ↑Collagen ↑Chondroitin Sulphate ↑Cell Size and Number ↑Linear Growth

9. Daily GH Levels (24hr)

10. Somatomedin-C (IGF-1) LevelsPeak about 1 yr after PHV

11. Growth Plate

12. GH & IGF Interactions in Long Bone Growth Stimulates proliferation of chondrocyte precursors and thus expands the proliferative chondrocyte pool and the hepatic and/or local production of IGF-1 Germinal Zone GH IGF-2 Proliferative Zone IGF-2 IGF-2 IGF-2 Stimulates clonal expansion by autocrine/paracrine mechanisms Promotes chondrocyte hypertrophy Hypertrophic Zone IGF-1

13. Hypopituitarism • 16 year old boy with hypopituitarism due to craniopharyngioma • Height = 137 cm

14. Acromegaly Greek akros "extreme" or "extremities" and megalos "large"

15. Andre the Giant

16. Yao Ming

17. Jaws – James Bond Movie • Richard Kiel • 7’ 1.5” • The Spy Who Loved Me, 1977

19. Thyroid • 3–4 weeks of gestation, the thyroid gland appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue • Over the next few weeks, it migrates to the base of the neck, passing anterior to the hyoid bone.

20. Thyroid • Thyrotropin-releasing factor (TRF) and thyroid-stimulating hormone (TSH) start being secreted from the fetal hypothalamus and pituitary at 18-20 weeks of gestation • Fetal production of thyroxine (T4) reach a clinically significant level at 18–20 weeks. • Fetal triiodothyronine (T3) remains low until 30 weeks of gestation • Fetal thyroid hormones tend to protect the fetus against brain development abnormalities caused by maternal hypothyroidism.

22. Goiter “Derbyshire neck”

23. Thyroid Hormones • TSH (Thyrotropin) from Ant. Pituitary stimulates production of Thyroxine • Tri-iodothyronine is mainly produced in target peripheral tissues from Thyroxine • Tri-iodothyronine is more potent and rapidly acting being calorigenic (stimulate oxygen uptake and energy expenditure)

24. Thyroid Hormones • Essential for RNA synthesis • Increase in metabolic rate • Increased thyroxine causes: • weight reduction; • increased heart rate and force of contraction; • increased nervous system activity

25. Thyroid Hormones • Cretins seldom appear hypothyrotic until several weeks after birth but do have retarded bone growth at birth • They can have irreparable brain damage although therapy was started within 1 or 2 months

26. 8 day old twins • most athyrotic children are born with normal size but retarded bone development • Athyrotic (left) • 3.5 kg, 53cm • Euthyrotic (right) • 2.9 kg, 50cm

27. Hyperthyroidism • Graves’ disease • Autoimmune disease • Exopthalmus “bug-eyes” • High metabolic Rate • Early death from heart attacks Marty Feldman -”bug-eyed” British comedian • Died at 39 of a heart attack • Video– Young Frankenstein

28. Parathyroids

29. Parathyroids - Parathormone • Essential for regulation of calcium and phosphate metabolism • Particularly important for normal bone and tooth development • Maintains stable plasma calcium concentrations by stimulating osteoclastic activity • Thyrocalcitonin (from thyroid) has opposite effects

30. Pancreas

31. Pancreas

32. INSULIN • CARBOHYDRATES • used preferentially and excess is stored as fat • ABSENCE OF INSULIN • Fatty acids are mobilized and utilized in place of carbohydrates

33. Potent effects of Insulinon Protein Metabolism • Increased rate of transport of amino acids through cell membrane • Increased formation of RNA • Increased formation of protein by ribosomes

34. Complex Interaction between GH and Insulin ↑ HGH ↑ Protein Synthesis ↑ Growth Protein Intake ↓↑Caloric Storage ↑ IGF-1 ↑ Insulin

35. ↓ HGH ↓↑ Protein Synthesis ↓↑Growth Carbohydrate Intake ↑Caloric Storage ↓↑IGF-1 ↑ Insulin

36. ↑ HGH ↓ Protein Synthesis ↓ Growth Fasting ↑Caloric Mobilization ↓ IGF-1 ↓ Insulin

37. Insulin Imbalance Insulin Deficiency • Can retard growth nearly as much as GH deficiency Hyperinsulinism • Can result in accelerated growth • (but also accelerated maturity rate)

38. Gonadal Growth • The size and structure of the gonads does not change much prior to puberty.

39. Gonadal Hormones • Both sexes: Androgens & estrogens (adrenals) in small, constant levels in the urine • Gonadotrophins from Ant. pituitary stimulate development and function of the gonads • Androgens and Estrogens also produced by Adrenals. • Increased production at puberty.

40. Biological Activity of Androgens • Relative influence of gonadal or adrenal sources unknown. • Testicular androgens have greater biological activity than adrenal androgens • Young castrates: Adrenals not able to compensate for lost testicular production • IN FEMALES: After puberty most androgenic effects are produced by the adrenals • Majority of testosterone produce in the liver • IN MALES: Testes secrete estrogens

41. Sexual Development • Males and females follow the same pattern of growth to 6 weeks of gestation • At 12 weeks sex can be determined by external appearance

42. Sexual Development • Removal of gonads leads to female development • Local application of high concentrations of androgens causes: • development of Wolffian elements; no effect on mullerian elements • Destruction of one testis can lead to: • normal male development on unaffected side mullerian structures developing on affected side

44. FSH

45. LH

46. Testosterone • FSH (ICSH (ant. pit.)) causes release of testosterone • Androgens are also produced by the testes

47. Sex Steroids

48. More related to maturation

49. Metabolic action of Testosterone • Protein anabolism dependent on critical level of insulin • increased protein formation • increased cholesterol, triglycerides and F.F.A. production • decrease in phospholipids • increased retention of sodium, chlorides & potassium • increased muscular development

50. Metabolic action of Testosterone • Increased rate of skeletal maturation and closure of epiphyses. • closure of epiphyses more affected than linear growth • greater effect closer to puberty • facial development • Spermatogenesis complete 2 to 3 years after puberty.