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

Ai-Min Bao, M.D. Ph.D.

Zhejiang University School of Medicine

The HPG axis

The HPT axis

The HPA 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.

• 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

Endocrine versus Nervous system

Function - homeostatic mechanisms:

regulation of body temperature, water balance, and energy production;

regulation of the behavioral drives of thirst, hunger, and sexual behavior.

(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.)

rostal caudal

SCN

SON

PVN

NBM

III

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.

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）

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

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

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

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

•

•

Short loop – influence of hypothalamus by an anterior pituitaryhormone

Long loop – inhibition of anterior pituitary and/or hypothalamusby hormone secreted by third endocrine gland

• 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

Hypophysis = pituitary

Subdivided into the pars distalis, pars intermedia and pars tuberalis

The anterior lobe (adenohypophysis)

At the median eminence, neurons release regulatory factors through fenestrated capillaries

- Releasing hormones- Inhibiting hormones

The Pituitary Gland - Anterior Pituitary Hormones

MSH (pars intermedia )

The Pituitary Gland - Anterior Pituitary Hormones

The Pituitary Gland - Posterior Pituitary 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

Posterior Pituitary and hormones

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.

ADH function

Water retention: Target organ - ADH-sensitive cells in distal tubules & collectingducts of renal medulla; ADH binds to V2 receptors, enhances permeability of cellmembrane to water by AQP2.

Increase vascular tone: Target organ - arteriolar smooth muscle cells; ADH binds to V1A receptors, vasoconstriction; also named Arginine Vasopressin (AVP)

Regulation of ADH secretion

↑osmolality → ↑ secretionIncreased extracellular fluid osmolarity reduces size of osmoreceptors located in hypothalamus, which in turn stimulates ADH secretion

↑ blood volume → ↓secretionADH release is also controlled by cardiovascular reflexes in response to blood volume (atrial receptors) /pressure changes

OXTSynthesis: 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

Review: Regulation by Negative Feedback

Three Methods of Hypothalamic Control over the Endocrine System

Hormone Effects on Gene Activity

• 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

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)

Hormones of the adenohypophysis

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

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

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 )

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

Somatomedins (生长介素 )The growth-promoting effects of GH are mediatedby somatomedins

The effects of somatomedin are similar to that ofinsulin: 胰岛素样生长因子 Insulin-like growth factor(IGF)IGF-I & IGF-II are produced in many tissues, withautocrine, paracrine, and endocrine functions

The major source of circulating IGFs is the liver

IGF-I synthesis is GH-dependent, IGF-II synthesisis less GH-dependent

Fasting or insulin deficiency leads to diminishedliver production of IGFs despite increases in GHsecretion GH － IGF-1 axis

GH related hormone

• Deficiency: dwarfism• Excessive: gigantism (child), acromegaly (adult)

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

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

Physiological Functions of Growth Hormone

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

Dwarfism & GigantismYoung female dwarf standing next to a boy of normal stature.

肢端肥大症

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

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

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

Factors that Control GH Secretion

ProlactinHuman 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

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

Melanocyte-stimulating hormone (MSH)

May be secreted by the pars intermedia during fetal development, early childhood, pregnancy or certain diseases

Stimulates melanocytes to produce melanin

Types– α-MSH, β-MSH （人） , γ-MSH

Effect– ↑黑素细胞 (melanophores) 黑色素生成，使黑色素颗粒在细胞内分散– 可能参与调节 GH 、醛固酮、 CRH 、胰岛素、 LH 等分泌Regulation– MIF– MRF

Pro-opiomelanocortin (POMC,阿黑皮素原 )a precursor hormone with 241 amino acid residues from corticotrophs in anterior pituitary,also synthesized by other tissues, e.g. placenta, GIprecursor for ACTH, β-lipotropin (β-LPH), γ-lipotropin (γ-LPH), β-endorphin, N-terminal peptide, MSH (α-MSH within ACTH, β-MSH within γ-LPH, and γ-MSH within N-Peptide)

Pro-opiomelanocortin (POMC) - a precursor polypeptide, synthesized from the 285-aa polypeptide precursor, pre-pro-opiomelanocortin (pre-POMC), by the removal of a 44-aa signal peptide sequence during translation.