Download 包爱民_下丘脑与垂体的内分泌功能

Ai-Min Bao, M.D. Ph.D.
Zhejiang University School of Medicine
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.
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
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
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.
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（melanophorestimulating hormone releasing factor, MRF;
melanophore-stimulating hormone releaseinhibiting 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 pituitary
hormone
•
Long loop – inhibition of anterior pituitary and/or hypothalamus
by hormone secreted by third endocrine gland
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
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
The Pituitary Gland - Anterior Pituitary Hormones
MSH (pars intermedia )
The Pituitary Gland - Anterior Pituitary Hormones
The Pituitary Gland - Posterior Pituitary Hormones
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
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 & 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)
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
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
Review: Regulation by Negative Feedback
Three Methods of Hypothalamic Control over the Endocrine System
Hormone Effects on Gene Activity
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
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)
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 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
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 crossreact 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 & Gigantism
Young 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
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
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, GI
precursor 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.