Principles of Endocrinology - Fudan...
Transcript of Principles of Endocrinology - Fudan...
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Principles of Endocrinology
Department of Endocrinology and Metabolism
Zhongshan Hospital
Fudan University
凌 雁 Yan Ling
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Scope of endocrinology
Endocrinology is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions called hormones.
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Function of Endocrine system
Endocrine system, composed of endocrine gland
(classical) and cells (non-classical), independently or
along with nervous system and immune system,
coordinate complex body functions, such as
metabolism, growth and development,
reproduction etc.
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Endocrine glands and organs containing endocrine cells
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Endocrine and Exocrine
Hormone
Endocrine cells
Duct
Sweat gland
Endocrine
Exocrine
-- Ductless
-- well vascularised
-- secrete hormones
into extracellular fluid
or blood
Endocrine gland
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Endocrine and neuroendocrine: a chemical released by a specialized group of cells into the circulationand acting on a distant target tissue.
Paracrine: chemical communication between neighboring cells within a tissue or organ.
Autocrine: a chemical acts on the same cell
Intracrine: a chemical acting within the same cell.
Endocrine, paracrine, autocrine and intracrine
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Outlines
Part 1: Introduction of hormone
Part 2: Hypothalamus, pituitary and their hormones
Part 3: Regulation of hormones secretion
Part 4: Endocrine diseases
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Functional chemical messengers in endocrine system
Definition and characteristics
Hormone secretion and transport
Mechanisms of hormone actions
Hormone
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Definition of Hormone
Hormone is bioactive chemical messenger released
from endocrine cells, and carried by extracellular
fluid or blood to target cells throughout the body. By
binding to its receptor, hormone initiates multiple
reactions.
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Characteristics of hormone
Specificity
Signaling
High effective
Cooperation
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Chemical classification of hormones
Amino acid derivatives
• Dopamine, catecholamines, and thyroid hormone
Small neuropeptides
• Gonadotropin-releasing hormone(GnRH), thyrotropin-releasing hormone (TRH), somatostatin, and vasopressin
Large proteins
• Insulin, luteinizing hormone (LH), and parathyroid hormone (PTH)
Steroid hormones
• Cortisol, estrogen
Vitamin derivatives
• Retinoids (vitamin A) and vitamin D
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Structure of hormones
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Hormone synthesis and processing – peptide hormones
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Hormone synthesis and processing – steroid hormones
Synthesis of most
steroid hormones is
based on
modifications of the
precursor -
cholesterol.
Multiple regulated
enzymatic steps are
required for the
synthesis of
testosterone,
estradiol, cortisol,
and vitamin D.
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Transport of hormones in the circulation
Many hormones circulate in association with serum-binding proteins.
• Steroid and thyroid hormones are less soluble in aqueous solution than protein and peptide hormones and over 90% circulate in blood as complexes bound to specific plasma globulins or albumin.
Bound and free hormones are in equilibrium.
• T4 and T3 binding to thyroxine-binding globulin (TBG), albumin, and thyroxine-binding prealbumin (TBPA)
• Cortisol binding to cortisol-binding globulin (CBG)
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Transport of hormones in the circulation
• Unbound or free hormone is biologically active.
• Hormone binding delays metabolism and provides a circulating reservoir of hormones.
• Alterations in the serum concentrations of binding proteins alter total serum concentrations of a hormone but may have much less effect on the concentrations of free hormone.
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Half-lives of hormones
• The half life (t½) of catecholamines is in the order of seconds, minutes for protein and peptide hormones and hours for steroid and thyroid hormones.
• An understanding of circulating hormone half-life is important for achieving physiologic hormone replacement.
• T4 has a half-life of 7 days. >1 month is required to reach a new steady state, but single daily doses are sufficient to achieve constant hormone levels.
• T3 has a half-life of 1 day. Its administration is associated with more dynamic serum levels and it must be administered two to three times per day.
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Functions of hormones
Growth
• GH
• IGF-1
• Thyroid hormone
• Sex steroids
Reproduction
• Sex determination and sexual maturation
• Conception, pregnancy, lactation and child-rearing
Maintenance of homeostasis
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Hormones and homeostasis
• Thyroid hormone - controls about 25% of basal metabolism in most tissues
• Cortisol - exerts a permissive action for many hormones in addition to its own direct effects
• PTH - regulates calcium and phosphorus levels
• Vasopressin - regulates serum osmolality by controlling renal free water clearance
• Mineralocorticoids - control vascular volume and serum electrolyte (Na+, K+) concentrations
• Insulin - maintains euglycemia in the fed and fasted states
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Mechanisms of hormone action
Step 1: Binding to receptors
Step 2: Intracellular signaling cascade
Step 3: Final physiological response
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Hormone receptors
Cell-surface membrane receptors
• Amino acid derivatives and peptide hormones
Intracellular nuclear receptors
• Steroids, thyroid hormones, vitamin D, and retinoids
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Membrane Receptor Families
• G protein–coupled seven-transmembrane receptor (GPCR)
• β-Adrenergic, LH, FSH, TSH, Glucagon, PTH, PTHrP, ACTH, MSH, GHRH, CRH, α-Adrenergic, Somatostatin, TRH, GnRH
• Receptor tyrosine kinase
• Insulin, IGF-I, EGF, NGF
• Cytokine receptor–linked kinase
• GH, PRL
• Serine Kinase
• Activin, TGF-β, MIS
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G protein–coupled seven-transmembrane receptor (GPCR)
G-protein linked receptors that frequently activate serine/threonine kinases
through second messengers such as cAMP, diacylglycerol, calmodulin
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G protein–coupled seven-transmembrane receptor (GPCR)
• When hormone binding to the receptor, G protein’s α subunit
• Releases GDP, binds GTP
• Dissociates from its β γ subunits & the receptor
• Binds & activates/inhibits effector (adenyl/guanylate cyclase, phospholipase C)
• Hydrolyzes GTP to GDP
• Re-associates with its β γ subunits
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Receptor tyrosine kinase
Receptors with inherent tyrosine kinase activity or associated with intracellular
molecules possessing tyrosine kinase activity. Some intracellular kinases are
attached to the membrane.
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Insulin receptor and intracellular signaling pathways in skeletal muscle
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Mechanism of thyroid hormone receptor action
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Outlines
Part 1: Introduction of hormone
Part 2: Hypothalamus, pituitary and their hormones
Part 3: Regulation of hormones secretion
Part 4: Endocrine diseases
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Location and Structure of Pituitary
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Nucleus in Hypothalamus
Specific areas that produce and release
multiple hormones
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Relations between Pituitary and Hypothalamus
Vasopressin and oxytocin are
synthesized in hypothalamus but
released in posterior pituitary
(green).
Hormones produced in
hypothalamus are carried via
hypothalamic-hypophysial portal
system to anterior pituitary and
regulate the endocrine cells activity
in the anterior pituitary (red).
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Hypothalamus-pituitary-target glands axes
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Outlines
Part 1: Introduction of hormone
Part 2: Hypothalamus, pituitary and their hormones
Part 3: Regulation of hormones secretion
Part 4: Endocrine diseases
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Hormonal rhythms
Feedback control (Negative and positive)
Neuroendocrine interactions
Cross-talk with immune system
Regulation of hormones secretion
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Hormonal rhythms
• Rhythms
• circadian
• light/dark fine/tune endogenous rhythm of cells & suprachiasmatic nucleus of hypothalamus
• Pituitary hormones, melatonin, cortisol
• monthly
• seasonal (day length; atavistic)
• developmental (puberty, menopause)
• Pulsations/oscillations
• GnRH, gonadotropins
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Circadian and pulsatile secretion of ACTH and cortisol
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Changes in the ovarian follicle, endometrial thickness, and
serum hormone levels during a 28-day menstrual cycle.
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Hormonal rhythms
• Recognition of these rhythms is important for endocrine testing.
• The HPA axis exhibits characteristic peaks of ACTH and cortisol production in the early morning, with a nadir during the night.
• As cortisol is normally high in the morning, morning cortisol levels are similar in Patients with Cushing's syndrome and normal individuals.
• Patients with Cushing's syndrome characteristically exhibit increased midnight cortisol levels when compared to normal individuals.
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Hormonal rhythms
• Recognition of these rhythms is important for glucocorticoids treatment.
• The HPA axis is more susceptible to suppression by glucocorticoids administered at night as they blunt the early morning rise of ACTH.
• Glucocorticoid replacement that mimics diurnal production by administering larger doses in the morning than in the afternoon
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Hormonal rhythms
• When relating serum hormone measurements to normal values, one should be aware of the pulsatile nature of hormone secretion and the rhythmic patterns of hormone production.
• Integrated markers have been developed to circumvent hormonal fluctuations.
• 24-h urine collections for cortisol
• IGF-I as a biologic marker of GH action
• HbA1c as an index of long-term blood glucose control
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Hypothalamic–pituitary–negative feedback
• Thyroid hormones feedback on the TRH-TSH axis
• Cortisol feedback on the CRH-ACTH axis
• Gonadal steroids feedback on the GnRH-LH/FSH axis
• IGF-I feedback on the GHRH-GH axis
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Feedback regulation not involve pituitary
Calcium feedback on PTH
Glucose feedback on insulin
Leptin feedback on hypothalamus
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Feedback regulation of Hormones in classic endocrine pathways
Principles of feedback control in the endocrine system
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Hypothalamus-pituitary-thyroid axis
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Neuroendocrine interactions
• All endocrine glands are innervated by autonomic nerves and these may either directly control their endocrine function and/or regulate blood flow (and hence function) within the gland.
• Hormones, in turn, may affect central nervous system functions such as mood, anxiety and behavior.
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Neuroendocrine interactions
• Neurosecretory cells may directly convert a neural signal into a hormonal signal.
• Activation of neurosecretory cells leads to secretion of a hormone into the circulation.
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Neuroendocrine interactions
• Neurosecretory cells include:
• Cells that secrete hypothalamic releasing and inhibiting hormones controlling TSH, ACTH, LH and FSH release from the anterior pituitary gland.
• The hypothalamic neurons the axon terminals of which secrete oxytocin and vasopressin from the posterior pituitary gland.
• The chromaffin cells of the adrenal medulla (embryologically modified neurons) that secrete epinephrine and norepinephrine into the general circulation.
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Neuroendocrine interactions
• The significance of these neurosecretory cells is that they allow the endocrine system to integrate and respond to changes in the external environment.
• The CRH-ACTH-cortisol axis can be activated by stress generated from external cues
• Oxytocin secretion by a suckling baby.
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Oxytocin & Prolactin
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Cross-talk between the endocrine system and the immune system
•Thymic hormones and
immunomodulators may
alter endocrine function
•Hormones may modulate
immune responses.
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Outlines
Part 1: Introduction of hormone
Part 2: Hypothalamus, pituitary and their hormones
Part 3: Regulation of hormones secretion
Part 4: Endocrine diseases
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Endocrine disease
Endocrine diseases fall into three major categories:
Hormone excess
Hormone deficiency
Altered tissue responses to hormones
• Hormone resistance, activating mutations of receptors
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Hormone excess
Neoplastic growth of endocrine cells
Pituitary adenomas, hyperparathyroidism
Autoimmune disorders
Graves’ disease
Excess hormone administration
Iatrogenic Cushing’s syndrome
Infectious / inflammation
Subacute thyroiditis
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Hormone deficiency
Autoimmunity
Hashimoto’s thyroiditis, type 1 diabetes, Addison’s disease
Iatrogenic
Radiation, sugery
Infection / inflammation
Adrenal tuberculosis, hypothalamic sarcoidosis
Infarction / hemorrhage
Sheehan’s syndrome
Enzyme defects
Congenital adrenal hyperplasia
Nutritional deficiency
Iodine deficiency, vitamin D deficiency
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Thyroid hormone excess – Graves’ disease
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Thyroid hormone deficiency - hypothyroidism
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Growth hormone excess – acromegaly and gigantism
Before At admission
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Growth hormone deficiency - Dwarfism
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Addison, Thomas 1793-1860
γMSH
Pro-opiomelanocortin (POMC)
αMSH βMSH
ACTH
Addison’s disease
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Diagnosis of endocrine disease
Principles of diagnosis
• Functional diagnosis
• Localization
• Etiologic/Pathologic diagnosis
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Functional diagnosis – measurement of hormones
Diagnosis is based on the measurement of hormone concentrations in venous serum or body fluids such as urine or saliva.
Interpretation of the results of these assays should always take into account three factors:
• The clinical features of the patient
• The concentration of the variable regulated by the hormone
• The concentration of other hormones in the feedback loop
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Functional diagnosis – measurement of hormones
Correct interpretation of thyroid, adrenal or gonadal hormone concentrations requires the results of the appropriate pituitary hormone concentrations.
• When T3 and T4 concentrations are low, TSH should be evaluated.
• TSH is elevated – primary hypothyroidism
• TSH is decreased – secondary hypothyroidism
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Functional diagnosis – measurement of hormones
Factors effect the measurement of hormones
• Gender
• Age
• Pulsatile nature of hormones
• Sleep
• Meals
• Medications
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Functional diagnosis – dynamic tests
• When baseline hormone associated with pathologic conditions to overlap with the normal range
• In situations of suspected endocrine hyperfunction, suppression tests are used
• The dexamethasone suppression test in Cushing’s syndrome
• In situations of suspected endocrine hypofunction, stimulation tests are used
• The ACTH stimulating test in adrenal insufficiency
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Feedback regulation of endocrine axes
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Treatment of endocrine diseases
• Endocrine hyperfunction
• Removing tumors surgically
• Reducing hormone levels medically
• Endocrine hypofunction
• Physiologic hormone replacement
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Thank you!