Ai-Min Bao, M.D. Ph.D. Zhejiang University School of Medicine

1. Ai-Min Bao, M.D. Ph.D. Zhejiang University School of Medicine

2. The HPT axis The HPA axis The HPG axis The endocrine system differs from most of the other organ systems of the body - the various glands are not anatomically connected; however, they do form a system in the functional sense.

3. Endocrine versus Nervous system • Nervous system performs short term crisis management • Endocrine system regulates long term ongoing metabolic • Endocrine communication is carried out by endocrine cells releasing hormones • Alter metabolic activities of tissues and organs • Target cells • Paracrine communication involves chemical messengers between cells within one tissue

5. Function - homeostatic mechanisms: regulation of body temperature, water balance, and energy production; regulation of the behavioral drives of thirst, hunger, and sexual behavior.

6. (A) Magnetic resonance image (MRI) and (B) corresponding schematic illustration of the human hypothalamus and pituitary gland seen in saggital plane. Note the high intensity or "bright spot" of the posterior pituitary by MRI in (A), sharply defining the boundary between the anterior pituitary gland. (Modified from Lechan RM. Neuroendocrinology of Pituitary Hormone Regulation. Endocrinology and Metabolism Clinics 16:475-501, 1987.)

7. rostal caudal

8. III NBM PVN SON SCN Both human PVN and SON contain about 50.000 neurons. Almost all vasopressinergic SON neurons project to the posterior pituitary thus influencing plasma levels. In the PVN there are 3 different types of vasopressin producing neurons. Some take part in the HPA-axis, some project to the neuropituitary, some to other brain areas.

9. Hypothalamus Neuroendocrine cell (神经内分泌细胞) – Parvocellular neurosecretory system （小细胞神经内分泌系统） – Magnocellular neurosecretory system （大细胞神经内分泌系统） – Supervisory cell （监察细胞）

10. Hypothalamus Parvocellular neurosecretory cell (PvC) 神经内分泌小细胞 – Hypophysiotrophic area, HTA 下丘脑促垂体区 • 调节腺垂体内分泌活动 Magnocellular neurosecretory cell (MgC) 神经内分泌大细胞 – 视上核、室旁核 – 神经垂体激素－催产素、血管加压素 – 神经垂体激素运载蛋白I, II (Neurophysin I, II) – 神经肽：脑啡肽、内啡肽、神经肽Y

11. Hypothalamic Hormone Hypothalamic regulatory peptide – Hypothalamic releasing/inhibitory hormones Neurohormone 神经垂体激素 – ADH or vasopressin – Oxytocin Pituitary adenylate cyclase-activating polypeptide PACAP 垂体腺苷酸环化酶激活肽 – 视上核、室旁核－垂体柄、正中隆起 – 旁分泌方式调节腺垂体细胞生长、分化和分泌

12. The Hypothalamus - Hormones and Releasing Factors Prolactin Releasing Hormone (PRH) Prolactin Inhibiting Hormone (PIH) Thyrotropin Releasing Hormone (TRH)Corticotropin Releasing Hormone (CRH)Gonadotropin Releasing Hormone (GnRH) Growth Hormone Releasing Hormone (GHRH)Growth Hormone Inhibiting Hormone (GHIH) 促黑素细胞激素释放/抑制因子（melanophore-stimulating hormone releasing factor, MRF; melanophore-stimulating hormone release-inhibiting factor, MIF)可能是催产素裂解出来的两种小分子肽

13. Regulation of hypothalamic hormones 神经调节: – 单胺类递质: DA, NE, 5-HT – 肽类物质: 脑啡肽、β-内啡肽、神经降压素、P物质、VIP 下级激素的反馈效应

14. • • Short loop – influence of hypothalamus by an anterior pituitary hormone Long loop – inhibition of anterior pituitary and/or hypothalamus by hormone secreted by third endocrine gland

15. Hypophysis = pituitary • Releases 9 important peptide hormones • All 9 bind to membrane receptors and use cyclic AMP as a second messenger • Anterior pituitary originates from epithelium; posterior pituitary from neural tissue

16. The anterior lobe (adenohypophysis) Subdivided into the pars distalis, pars intermedia and pars tuberalis At the median eminence, neurons release regulatory factors through fenestrated capillaries - Releasing hormones - Inhibiting hormones

17. The Pituitary Gland - Anterior Pituitary Hormones MSH (pars intermedia)

18. The Pituitary Gland - Anterior Pituitary Hormones

19. The Pituitary Gland - Posterior Pituitary Hormones

20. Posterior Pituitary and hormones • Contains axons of hypothalamic nerves • neurons of the supraoptic nucleus (SON) and paraventricular nucleus (PVN) manufacture antidiuretic hormone (ADH = vasopressin, AVP), oxytocin (OXT) and Neurophysin (NP，后叶激素运载蛋白) • ADH decreases the amount of water lost at the kidneys, elevates blood pressure • OXT stimulates contractile cells in mammary glands, stimulates smooth muscle cells in uterus Transportation: • NP-1 + OT; NP-2 + VP • in axoplasm of the neuron’s fibers Release: Exocytosis

21. The structural and chemical characteristics of AVP and OXT The cyclical peptides differ in only 2 amino acid positions Both contain disulphide bridges between Cysteine residues (半胱氨酸残基) at positions 1 and 6.

22. ADH function Water retention:Target organ - ADH-sensitive cells in distal tubules & collecting ducts of renal medulla; ADH binds to V2 receptors, enhances permeability of cell membrane to water by AQP2. Increase vascular tone:Target organ - arteriolar smooth muscle cells; ADH binds to V1A receptors, vasoconstriction; also named Arginine Vasopressin (AVP)

23. Regulation of ADH secretion ↑osmolality → ↑ secretion Increased extracellular fluid osmolarity reduces size of osmoreceptors located in hypothalamus, which in turn stimulates ADH secretion ↑ blood volume → ↓secretion ADH release is also controlled by cardiovascular reflexes in response to blood volume (atrial receptors) /pressure changes

24. OXT Synthesis: SON, PVN Secretion: Parturition, lactation, coition Function: - Contraction of the uterus * induces labor contraction ** reduces postpartum bleeding - Contraction of myoepithelial cells in the breast stimulates milk ‘let-down’ Regulation - Neuroendocrine reflex (Milk ejection reflex) * Suckling - Positive feedback - Acute stress • (-) OTX secretion • * Levels of sex steroids

26. Review: Regulation by Negative Feedback

27. Three Methods of Hypothalamic Control over the Endocrine System

30. Hormone Effects on Gene Activity

31. Hormones of the adenohypophysis • Thyroid stimulating hormone (TSH) • Triggers the release of thyroid hormones • Thyrotropin releasing hormone promotes the release of TSH • Adrenocorticotropic hormone (ACTH) • Stimulates the release of glucocorticoids by the adrenal gland • Corticotrophin releasing hormone causes the secretion of ACTH • Follicle stimulating hormone (FSH) • Stimulates follicle development and estrogen secretion in females and sperm production in males • Leutinizing hormone (LH) • Causes ovulation and progestin production in females and androgen production in males • Gonadotropin releasing hormone (GnRH) promotes the secretion of FSH and LH

32. Hormones of the adenohypophysis • Prolactin (PRL) • Stimulates the development of mammary glands and milk production • Growth hormone (GH or somatotropin) • Stimulates cell growth and replication through release of somatomedins or IGF • Growth-hormone releasing hormone (GH-RH) • Growth-hormone inhibiting hormone (GH-IH)

33. Growth Hormone • Also called somatotropin, mostly secreted at night • Acts on target cells in the liver, the liver then produces other hormones called somatomedins • Significant effects on metabolism: • Increased amino acid uptake and protein synthesis • Mobilization of fatty acids from adipose tissue • Enhances glycogen breakdown (called glycogenolysis), decreases rate of glucose utilization in most cells • Diabetogenic effect: blood glucose levels rise, as more glucose is being released from glycogen stores but less glucose is being used by cells hGH – 191 amino acids

34. Metabolic Effects of GH Anabolic – increase amino acid uptake, protein, RNA/DNA synthesis – decrease amino acid/protein degradation Ketogenic – increase lipolysis – increase fatty acid oxidation→ketones Diabetogenic – increase plasma glucose ( ↓uptake &↑gluconeogenesis) – increase insulin secretion

35. Growth Hormone - Circulates in 2 forms (22-kDa & 20-kDa) of similar biologic activity - promotes growth of body tissues by increasing the size & numbers of cells - Homologous with prolactin and human placenta lactogen (hPL, 胎盘催乳素) Somatostatin (Growth hormone-inhibiting Hormone, somato-tropin release inhibiting hormone) Somatostatin Inhibit the release of glucagon, insulin, and gastrin(胃泌素)

36. Studies by Salmon and Daughaday in 1957demonstrated that GH needs a ‘mediator’ for its growth-promoting action

37. Somatomedins (生长介素) The growth-promoting effects of GH are mediated by somatomedins The effects of somatomedin are similar to that of insulin: 胰岛素样生长因子Insulin-like growth factor (IGF) IGF-I & IGF-II are produced in many tissues, with autocrine, paracrine, and endocrine functions The major source of circulating IGFs is the liver IGF-I synthesis is GH-dependent, IGF-II synthesis is less GH-dependent Fasting or insulin deficiency leads to diminished liver production of IGFs despite increases in GH secretion GH－IGF-1 axis

38. GH related hormone • Deficiency: dwarfism • Excessive: gigantism (child), acromegaly (adult)

39. IGF Binding Proteins 40% GH in circulation is bound to GHBP, more than 90% IGF-I in circulation is bound to IGFBP IGFs are more stable than GH in plasma Half-life: IGF-I (20 hours), GH (20 minutes) Plasma IGF-I level is a valuable measurement of GH secretion IGF binding proteins (IGFBP1-6) - Transport IGFs - Serve as a large reservoir - Prevent degradation of IGFs

40. IGF Receptors Receptor of IGF-I is a dimer, structurally similar to the insulin receptor and has intrinsic tyrosine kinase activity The receptor of IGF-II is a monomer IGFs and insulin cross-react with each other’s receptor, although with lower affinities

41. Physiological Functions of Growth Hormone

42. Abnormalities of GH • Dwarfism: decreased secretion of hormone (prolonged steroid use) or decreased number of receptors (African pigmies) • Gigantism: excess secretion before epiphyseal plates close • Acromegaly: excess secretion after epiphyseal plates close Young female dwarf standing next to a boy of normal stature. Dwarfism & Gigantism

44. 肢端肥大症

45. Photograph of a patient with the classical face of Laron Syndrome, or Laron-type dwarfism, an autosomal recessive disorder characterized by an insensitivity to growth hormone (GHIS), caused by a variant of the GH receptor; Short stature and a resistance to diabetes and cancer; Mutations in the gene for the GH receptor. There are exceptionally low levels of IGF-1 and its principal carrier protein, IGFBP-3; A related condition involving post-receptor insensitivity to growth hormone has been associated with STAT5B

46. Review: Regulation of GH Secretion 下丘脑GHRH, GHIH（SS）调节 GH 和 IGF反馈调节 睡眠时相 代谢因素饥饿、运动、应激、情绪紧张

47. Action of GHRH and GIH GHRH – ↑GH合成、分泌 生长激素释放肽Ghrelin – 来源：胃粘膜内分泌细胞、下丘脑弓状核 – 调节肽（28aa） – 作用 • 类似GHRH作用 • 促进食欲和生长发育 GIH or SS – ↓GH合成、分泌

48. Factors that Control GH Secretion

49. Prolactin Human PRL,199 amino acids 血清浓度: 成人基础浓度0.5～0.8μg/dL, 女性>男性； 青春期、排卵期升高；妊娠末期：20～50μg/dL 半衰期：20min 促进乳腺发育，引起和维持泌乳 妊娠期乳腺发育 腺泡发育：雌激素与孕激素起基础作用，PRL与胰岛素、甲状腺激素、皮质醇等起协同作用 高浓度的孕激素、雌激素抑制PRL的泌乳作用— 分娩后雌、孕激素水平下降，PRL发挥始动和维持泌乳的作用 乳汁主要成分：酪蛋白、乳糖、脂肪 PRL对卵巢活动具有双相调节作用，对男性性功能也有影响 — 高催乳血症可致性腺机能减退 参与应激反应、参与免疫调节

50. 催乳素分泌的调节 受下丘脑PRF与PIH（DA，占优势）的双重调节； 婴儿吸吮乳头的刺激可通过脊髓上传至下丘脑，导致PRF释放增多，使腺垂体PRL大量分泌; 其它刺激PRL分泌的因素：TRH, E, VIP, PrRP, 5-HT, 内阿片肽、应激、剧烈活动、 睡眠、性交