204

Thyroid Hormone
. 5003097
.
5003110
.

Outline
Thyroid hormone
- Physiology





- Pathophysiology:
Hyperthyroidism
Hypothyroidism
Euthyroidism
-
Hyperthyroidism
Hypothyroidism
Parathyroid hormone
- Physiology





- Pathophysiology:
Hyperparathyroidism
Hypoparathyroidism

Hyperparathyroidism
Hypoparathyroidism

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Thyroid Hormone
Physiology


2
isthmus 2,
3 cricoid 15-25 g
2
pharyngeal
pouches 1 2 endoderm
pharyngeal pouches 4 ultimobranchial body
pharyngeal pouch 5 parafollicular (C) cells
80120 mL/min ( 1
cardiac output) superior inferior thyroid (Superior
and inferior thyroid arteries)
Laryngeal pharyngeal

. Follicular cells (Follicles) 0.020.9
(villi) thyroid hormones Iodothyronines Thyroxine (T4) Triiodothyronine
(T3) metabolism thyroid follicle colloid
follicular cells thyroid hormones
2. Parafollicular cells C cells
follicles Thyrocalcitonin calcitonin
++
Ca

2
1. Thyroid hormones Iodothyronines tyrosine

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Thyroxine (T4) Triiodothyronine (T3) metabolism

T4 T3 T4 T3 T3
thyroid hormone reverseT3 (rT3)
2. Thyrocalcitonin calcitonin Ca++
Thyroid hormones Iodothyronines

TRH (Thyrotropin-releasing hormone)

TSH (Thyroid-stimulating hormone
thyrotropin) TSH
thyroid hormones
follicular
cells
Thyroid hormones (T4 T3)
(Negative feedback)
TSH
thyroid
hormones
thyroid hormones

thyroid hormones 4
1. thyroglobulin thyroglobulin glycoprotein tyrosine polysaccharide
Rough Endoplasmic Reticulum
2. (Iodide trapping) (I-)
Active transport autoregulation mechanism

3. tyrosine (Oxidation Organification)
peroxidase H2O2
tyrosine thyroglobulin monoiodotyrosine (MIT) diiodotyrosine (DIT)
organification

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4. Iodotyrosine (Coupling) MIT DIT

T4
DIT 2 T3 DIT MIT peroxidase
(Storage Secretion)
T4 T3

thyroglobulin thyroid
follicles TSH T4 T3 thyroglobulin Proteolysis
ECF (Secretion)
T4 T3 3 : 1 T4
7090 T3 1530
(Transportation)
T4 99.96 T3 99.5 3 thyroid-binding globulin
(TBG), thyroid-binding prealbumin (TBPA) albumin

thyroid hormone
T4
T3
Thyroid binding globulin (TBG)
70
77
Thyroid-binding prealbumin (TBPA)
10
8
Albumin
20
15
Thyroid binding protein

T4 (thyroxine) T3 (triiodothyronine) reverse T3

T3 reverse T3 (rT3) 80
T4 T4 (deiodination) enzyme monodeiodinase
Thyroid Hormone Synthesis and Secretion Inhibitors
Mechanism of Action
Compound

Inhibition of iodide transport into the

thiocyanate (SCN ), perchlorate (ClO4-),
pertechnetate(TcO4), Fluorine, Bromine, Lithium
thyroid
Inhibition of organification and coupling Thioureylenes (thioamides)
Inhibition of hormone secretion
Iodide, lithium (large doses)
Inhibition of deiodination of T4 to T3
Thioureylenes, -Adrenergic receptor blockers,
Glucocorticoids

T4 T3 T4 T3 thyroid hormone receptors

(nuclear receptors) target gene

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metabolism
- carbohydrate metabolism glycolysis gluconeogenesis

- protein metabolism thyroid Hormones

- fat metabolism lipolysis lipogenesis
- insulin

- basal metabolic rate

O2 ( O2 consumption)

-
- growth hormone
- parathyroid hormone

- thyroid hormone
- cardiac output

T4 T3 metabolised

free form conjugated form

T4 7 T3 1.5

Pathophysiology
(Thyroid disorder) 3 Hyperthyroidism Hypothyroidism
Euthyroid
1) Hyperthyroidism
Hyperthyroidism
hyperthyroidism
Thyrotoxicosis ( ) thyroid hormone
metabolism hyperthyroidism
thyroid hormone

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Hyperthyroidism
1. Toxic diffuse goiter (Graves disease)

hyperthyroidism
Autoimmune disease
immunoglobulin Thyroid Stimulating Immunoglobulin (TSI) autoantibody
TSH receptor autoantibody
Graves ophthalmopathy
immunoglobulin Long Acting Thyroid Stimulator (LATS)
LATS LATS
TSH 12
2. Toxic multinodular goiter (Plummers disease Toxic adenomas)

(Toxic adenoma)
thyroid hormone
3. Thyroditis
thyroid hormone leak

4. Iodine-induced hyperthyroidism
thyroid hormone

5. thyroid hormone
Hypothyroidism
Hyperthyroidism
- (nervousness)
- (anxiety)
- (palpitations)
- (hand tremor)
-
- (emotion liability)
- (heat intolerance)
-
- (insomnia)
-
- -
- (thyromegaly) -
-
-exophthalmos Graves disease
tachycardia

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2) Hypothyroidism
Hypothyroidism thyroid hormone

Hypothyroidism
1. Primary hypothyroidism thyroid hormone
1.1 Chronic autoimmune thyroiditis (Hashimotos disease)
Autoimmune disease antibodies enzyme thyroid
peroxidase, thyroglubolin thyroid cell TSH receptor

hypothyroidism Hashimotos disease

1.2 Itraogenic hypothyroidism

radioiodine hyperthyroidism Graves
disease hypothyroidism 3-12

.
(Thyroid hypoplasia)
thyroid hormone
2. Secondary hypothyroidism

thyroid hormone
2.1 Pituitary disease
TSH
Pituitary tumor, , Postpartum pituitary necrosis (Sheehans syndrome)

2.2 Hypothalamic Hypothyroidism

TRH hypothyroidism
Hypothyroidism
Hypothyroidism

-
- (Depression)
- (Muscle cramps)
-
-(myalgia)
-
-
-
- (cold intolerance)
-
-
-
-Bradycardia
-

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Hyperthyroidism Hypothyroidism
Hyperthyroidism Hypothyroidism
From: Damjanof I. Pathophysiology for the health professions. 3rded., Elsevier,2006

Free T4 index, free T3 index

- - adrenergic receptor
- insulin

- basal metabolic rate
- goiter
-
- activity
- reflexes
-
-

-
- myxedema
-

Hyperthyroidism

Hypothyroidism

Hyperactive, insomnia

Exophthalmos (Graves disease )

/
Lethargic ,somnolent

,
Hypercholesteroemia

3) Euthyroid
Euthyroid thyroid hormone TSH

Euthyroid
TSH

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Drug-Induced Thyroid Disease

Mechanism
Drugs that decrease TSH secretion
Drugs that alter thyroid hormone secretion
-Decreased thyroid hormone secretion
-Increased thyroid hormone secretion
Drugs that decrease T4 absorption
Drugs that alter T4 and T3 transport in serum
-Increased serum TBG concentration
-Decreased serum TBG concentration
-Displacement from protein-binding sites
Drugs that alter T4 and T3 metabolism
-Increased hepatic metabolism
-Decreased T4 5_-deiodinase activity
Cytokines

Drug
Dopamine, Glucocorticoids, Octreotide
Lithium Iodide, Amiodarone, Aminoglutethimide
Amiodarone
Colestipol, Cholestyramine, Aluminum hydroxide, Sucralfate,
Ferrous sulfate
Estrogens, Tamoxifen, Heroin, Methadone, Mitotane,
Fluorouracil
Androgens, Anabolic steroids (e.g. danazol),
Slow-release nicotinic acid, Glucocorticoids
Furosemide, Fenclofenac, Mefenamic acid, Salicylates
Phenobarbital, Rifampin, Phenytoin, Carbamazepine
Propylthiouracil, Amiodarone, Glucocorticoids,
Beta-adrenergicantagonist drugs
Interferon alfa, Interleukin-2

Thyroid disorders
- thyroid hormone thyroid hormone
- (Thyroid symptoms) (tenderness)
-

- Thyroid disorders
-

- target system thyroid hormone

- Thyroid/Antithyroid drugs
-Thyroid function test
Thyroid Function Test
Thyroid Function Test (Thyroid function)

. TSH
TSH
. T4
T4
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2.1 Total T4 (TT4) thyroid hormone

2.2 Free T (FT4) thyroid hormone T4

FT4 TT4
FTI4 (free thyroxine index) TT4 RT3U (resin T3 reuptake)

Hyperthyroidism

Hypothyroidism
Primary

Secondary

TSH

T4

3. T3
T3 Hyperthyroidism
Hyperthyroidism Hyperthyroidism T3 T3

Hypothyroidism T3 thyroid hormone

4. RT3U (Resin T3 uptake)

thyroid hormone
Total T Total T
thyroid function Free T (FT4) Free
T (FT3)
estrogen Euthyroid

thyroid binding protein total T4 total T3 thyroid hormone

resistance state T4 corticosteroids severe illness pituitary dysfunction
TSH

RAIU (131I radioactive iodine uptake) 131I radioactive iodine
131I hyperthyroidism
Thyroid antibodies ATgA (antibody to thyroglobulin) TPO (thyroperoxidase antibodies)
autoimmune TrAb (thyroid receptor IgG antibody) autoimmune
Graves disease Thyroid antibodies
Thyroid scan thyroid gland function
1. Hyperthyroidism
.
PE thyroid function test
- Weight and blood pressure
- Pulse rate and cardiac rhythm
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- Thyroid palpation and auscultation (thyroid size, nodularity, and vascularity)

- Neuromuscular examination
- Eye examination (exophthalmos or ophthalmopathy)
- Dermatologic examination
- Cardiovascular examination
- Lymphatic examination (nodes and spleen)
T3 T4 serum concentration TSH serum
concentration RAIU (radioactive iodine uptake) (differential diagnosis)

- TT4 ( - mcg / dL), FT ( . . ng / dL), TT3 ( - ng / dL)

- TSH ( . - . mlU / L)
- RT3U (Resin T3 uptake) ( %)

- antibody : TRab, ATgA
- RAIU( radioactive iodine uptake )
- cholesterol
- AST ALT
- Ca 2+
.
Hyperthyroidism
1. hyperthyroidism thyroid hormone TSH
2. thyroid storm
3. goiter
4. systemic embolism
5. (osteoporosis)
6.
7.
8.

antithyroid, , Radioactive iodine (RAI)

Antithyroid Drugs
Thioamides propylthiouracil (PTU) methimazole adjuncts
primary treatment Iodide containing preparation, beta blocker, CCB, steroid

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Thioamides
Mechanism of action

peroxidase

MIT DIT T4 T3 Propylthiouracil (PTU)
action Thyroid storm T4 T3 peripheral

Propylthiouracil (PTU) (URACIL mg / tab )

- onset methimazole thyroid hormone (thyroid storm)
Dose
- 6-10 50-150 3

- 10 150-300 3

-
300 3
400 600 900 3
100-150 3
5 7
3
Pregnancy Risk Factor D
Methimazole (MMI) (TAPAZOLE ,10 mg / tab )
- PTU 10 , half life PTU
Dose
- 0.4 1 3
0.2 1 30
- euthyroid
- 15 3 ( 8 )
30-40 60
5-15
Pregnancy Risk Factor D
Antithyroid
Agent

Bioavailability
(%)

Propylthiouracil
Methimazole

80 95
80 95

Protein
binding
(%)
75 - 80
0

Transplacental
passage

Breast milk
level (M:P)

Half-life
(hr)

Low
High

Low (0.1)
High (1)

12
6 13

Excreted
in urine
(%)
< 35
<10

- (Category D) PTU drugs of choice pregnancy breast feeding

methimazole

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Side effect
- (pruritic maculopapular rash) (arthralgia)
( 4000 ) benign transient leukopenia
thioureas MMI 50
- rare side effect (agranulocytosis)
(fever) (gingivitis) (malaise)
(oropharyngeal infection) granulocyte 500 ,
(aplastic anemia), (Lupus-like syndrome), (polymyositis),
(GI intolerance), (hepatotoxicity),
(hypoprothrombinemia) 3
agranulocytosis antibiotic
granulocyte count G-CSF thiourea

granulocyte count, CBC
Drugs Interaction
- Anticoagulant ( ) hypoprothrombinemia bleeding
- -Blocker -Blocker
- Digitalis glycoside ( ) digitalis
- Theophylline () theophylline hyperthyroid (
theophylline hypothyroid
C/I
- Hypersensitivity
Iodide-containing preparation (Inorganic iodine)
thyroid hormone negative feedback thyroid hormone
Lugol s solution 6.3 SSKI (Saturated
solution of potassium iodide) 38 thyroid storm
7 14
Mechanism of action
- iodide organification
-
-
Dose
SSKI 3 10 ( 120-140 )
7 14
Pregnancy Risk Factor X
Side effect
hypersensitivity reaction (skin rashes) (drug fever)
(rhinitis) (conjunctivitis), (salivary gland swelling),
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(iodism)
,
(gynecomastia)
Beta blocker, CCB, Steroid
Thioamide hyperthyroidism beta
blocker
(thyrotoxicosis)

TSAb euthyroid
propranolol block converse T4 T3 beta blocker CCB
Steroid steroid block converse T4 T3 peripheral thyroid storm
side effect
-Blocker (I131)
Graves disease (toxic nodule) ,
-Blocker

Pregnancy Risk Factor C (manufacturer); D (2nd and 3rd trimesters - expert analysis)
Radioactive iodine
131I, 125I 131I

Side effect
- Hypothyroidism , , ,
- high dose
C /I
,

- RAI 10 pregnancy test

- thioamide RAI
post-RAI hyperthyroidism, thyroid storm
- thioamide RAI 3 1-7 RAI uptake of 131I
- Iodide RAI

( second
trimester) , RAI euthyroid
Side effect
hypothyroidism,

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2. Hypothyroidism
.
PE thyroid function test
- TT4 ( - mcg / dL), FT ( . . ng / dL), TT3 ( - ng / dL)
- TSH ( . - . mlU / L)
- RT3U ( %)

- cholesterol ( total, LDL-C), CK, LDH, AST
- Hct / Hb
- Na

- psychosis
- / creatine phosphokinase(CPK)
- CHD
-
.
Hypothyroidism
. Hypothyroidism thyroid hormone TSH
2. long term consequences
Thyroid hormone replacement
-
T3 T4 %
-

: thyroid extract ( T3 T4 ) T4 L
thyroxine sodium (Eltroxin ) T3

Levothyroxine (L-thyroxine, T4)



levothyroxine
Mechanism of action
T3 levothyroxine T4
T4 converse T3
Dose
. . 1 ( ) half life 9-10
Drugs Interaction
- Anticoagulant,oral ( ) anticoagulant
- Cholestyramine, colestipol ()

- Digitalis glycoside ( ) glycoside

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- Iron salt () levothyroxine

hypothyroidism
- Theophylline () hypothyroidism theophyline

- Rifampin ( ), carbamazepine, phenytoin ()
T4 T3
- Amiodarone () T4 T3
levothyroxine
sucralfate()

- , Dose
recommend mcg / day
- osteoporosis,

Parathyroid Hormone
Physiology


2

(inferior parathyroid gland) pharyngeal
pouch 3 (superior parathyroid gland)
pharyngeal pouch 4 inferior
thyroid


(trabeculae)

2
1. Chief cell

chief cell
++
++
PTH Ca Ca
Calcitonin Ca++ Chief cells 2 dark chief cell light
chief cell
2. Oxyphil cell chief cell chief cell


chief cell transitional cells chief oxyphil cells
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Chief cells
(Calcium sensing receptor) - PTH
PTH (Negative feedback)

chief cell preProPTH (
)
N ProPTH

N PTH

PTH adenylate cyclase phosphatidylinositol pathway

protein kinase phosphorylation

PTH 3

- osteoblast osteoclast

-
-

- 25(OH)D3 1,25(OH)2D3

Endocrine regulators 3
PTH thyrocalcitonin PTH thyrocalcitonin

Pathophysiology

2 Hyperparathyroidism Hypoparathyroidism

1) Hyperparathyroidism
Hyperparathyroidism PTH
Hyperparathyroidism
1. Primary hyperparathyroidism PTH

2.
Secondary hyperparathyroidism PTH

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- ( Kyphosis ) osteoclast
- (hypercalcemia) hypercalciuria
hypophosphatemia
- HCO3-

(metabolic acidosis)
-

2) Hypoparathyroidism
Hypoparathyroidism PTH PTH

Hypoparathyroidism

Hypomagnesemia aminoglycosides

-
-
-
-
Trouesseaus sign
- (carpopedal spasm )
- ( Trouesseaus sign)
- laryngospasm

1. Hyperparathyroidism
1.
parathyroid immunoassay
serum calcium primary hyperparathyroidism secondary
hyperparathyroidism
PTH
Serum Calcium
hyperparathyroidism

Primary

Secondary
tertiary hyperthyroidism PTH serum calcium primary
hyperthyroidism tertiary hyperthyroidism

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hyperparathyroidism
facial
nerve (Chvosteks sign)
systolic ( Trouesseaus sign)
1.
(parathyroid adenoma)
hyperparathyroidism

secondary hyperparathyroidism
1.5
phosphate binding gel chronic alcoholism , malnutrition , aminoglycoside
( PTH
) calcitriol
- IV
D calcitriol

TH-One
(High Intensity Focused Ultrasound: HIFU)

primary hyperparathyroidism
secondary
hyperparathyroidism
calcimimetics cinacalcet primary
hyperparathyroidism secondary hyperparathyroidism



2. Hypoparathyroidism
2.
serum albumin
cAMP
hypoparathyroidism

- pseudohypoparathyodism (
) pseudopseudohypoparathyroidism (
pseudohypoparathyroidism
)
-

X
-
-
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(Electrocardiography: ECG)

facial nerve
(Chvosteks sign) systolic (
Trouesseaus sign)
.

calcium gluconate central venous catheter (
)


3 4 (
aminoglycoside )
phosphate binding gel

Teriparatide
hypoparathyroidism

Reference
1. , . Thyroid and antithyroid drugs Power point. :
; 2550.
2. . : , . .
3. : , 2535:288 294
3.
. . : . :
, 2551: 1-21.
4. . . : , 2550: 5-9.
5. . . : . : , 2551: 25-39.
6. . . : . : , 2551:
40-52.
7.
, . Thyroid diseases Power point. : ;
2550.
8. . . : , . . 3. :
, 2535: 187-206.
9. Joseph T., Robert L., Gary C. Yee, et al. Thyroid disorders. Pharmacotherapy 7th Ed. McGraw-Hill 2008; 78:1243-63
10. Laurence L., Keith L.Thyroid and anti thyroid drugs. Goodman&Gilmans. Manual of pharmacology and therapeutics. McGrawHill 2008; 981-94

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DiabetesMellitus
. 5003026
. 5003027
. 5003092
5103003 5103010 5103075

Outline

Physiology

Pharmacology & Clinical

Physiology
Islets of Langerhans
1.
(A)cell islets ( %) glucagon
2.
(B) cell islets ( %) insulin amylin
3.
D cell

islets ( - %) somatostatin
4.
F cell

islets ( %) pancreatin polypeptide

5.
G cell ( %) gastrin
hepatic portal vein

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. Insulin cell islet of Langerhans
. Glucagon cell Islet of Langerhans
Struture metabolism
Insulin peptide pro-insulin endopeptidase enzyme pro-insulin
Polyribosome endoplasmic recticulum -cell
Pro-insulin peptides A B C amino acid , 30 (porcine)
peptide A intra-disulfide bond Cys6 Cys11 Inter-disulfide bond
A B Cys7 , Cys7 Cys20 , Cys19 Peptide C pro-insulin
endopeptidase insulin peptides 2 A B disulfide
bond A

Insulin Pre-proinsulin peptide N-terminal

Pro-insulin endoplasmic recticulum Golgi apparatus cytoplasm
(secretion granule) (Zn) Pro-insulin
enzyme peptide peptide C
exocytosis peptide C
1:1 peptide C half life peptide
C B cell Half life proinsulin

proinsulin
300 unit 250 unit 50 unit
0.3-2 /.
8-10
30-40 90-120
Antibodies
antibodies Nonsuppressive insulin like activity NSILA IGF-1 , IGF-2 (insulin like growth)
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metabolism receptor IGF

IGF

Insulin 2
1. Basal insulin secretion insulin 0.5-1 unit/hr ( 70-120
mg/dl) (Preprandial glucose)

2. First and second phase insulin secretion insulin
(Prandial glucose) (Postprandial glucose)
first phase insulin secretion 5-10 second phase insulin secretion
glucose

Insulin
1. (glucose metabolism)
1) , ,
2) glycogen phosphorylase
3) glycogen synthase
4) glycerol ( gluconeogenesis)
2. (lipid metabolism)
1)
2) lipoprotein lipase triglycerides(TG) lipoprotein
3) lipoprotein
4) lipase TG TG
3. (protein metabolism)
1)
2)
3) ketone body
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Glucagon
glycogen adipose tissue
insulin uptake
(glycogen synthasis) glucagon receptor
glucagon (gluconeogenesis)

Glucose Homeostasis
50-100 mg%
Glucotoxicity (Glucotoxicity
insulin beta-cell beta-cell insulin first
phase insulin )

- -cell glucagon glucagon

glycogen ( glucose 85% 15%)

- -cell Insulin Insulin
glucose cell glycogen -- >

Glucose entry 2
1. exogenous glucose entry exogenous glucose entry
post prandial glucose 2
1) external factor
2) internal factor
GI tract, adipose tissue, adrenal gland )
2. endogenous glucose entry 2
gluconeogenesis gluconeolysis endogenous glucose entry fasting glucose
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Glucose utilization 2
1.
insulin
2.

(Polyuria) ,(Polydipsia) ,
(Polyphagia) , , ,,,

1 2
severe hyperglycemia insulin Counter regulatory hormone
catecholamines cortisol TG ketone body
Ketoacidosis

(dehydration) (hypotension) (tachycardia) (hyperventilation)
(hyperthermia) coma (~10%)

(Modifiable risk factors)

(Hyperglycemia) , (Hypertension BP>140/90) ,
(Dyslipidemia) ,Prothrombotic state , (Albuminuria) ,
(Smoking) , ,HDL <35, and/or TG>250 , (vascular dz.)
, cyst PCOS (polycystic ovarian syndrome) , other conditions associated with insulin
resistance , , 4 kg ,
American-African

- Type 1 diabetes
- Type 1.5 diabetes
- Type 2 diabetes
- Gestational Diabetes
- Other specific type , ,
Type 1 diabetes
- 1 cellular-mediated autoimmunity -cell T cell
-cell lymphocyte -cell -cell insulin insulin
insulin

- ketoacidosis( ketone glucose)

-
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- 1 (
40 ) 5-10% 1

- cellular-mediated autoimmune
- insulin
- Onset age < 40
- polyphagia(), polyuria(

), polydipsia()
-
-
- insulin
cellular-mediated autoimmune


1. HLA (Human leukocyte antigen)

.
-

autoreactive T cell
autoimmune
-

- regular T cell




- 1

Type 2 diabetes
2 Syndrome X Metabolic Syndrome
gout

ketoacidosis

macrovascular
microvascular

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- (insulin resistant)
(insulin deficiency)
-
- Onset age > 40 ( - )

-
-
-
-
Type 1.5 diabetes
Slow onset type 1 Latent Immune Diabetes in Adults(LADA)

islet cell antibodies

-
lipid profile
BMI
Type 2 diabetes
insulin
Gestational Diabetes
-
4%
-
-

insulin anabolic
( 4 kg)
- %
- % - 63% -
- side effects
Other specific type
-

- : steroid ,thiazide ,nicotinic acid ,thyroid hormone ,dilantin ,-adrenergic

agonist ,-interferon
- , ,

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Pharmacology and Clinical

1. Oral glucose tolerance test (OGTT) g 2
2. Random plasma glucose
3. Fasting plasma glucose (FPG)
4. A1C 6.5% standardize


1.

(random plasma glucose)
mg/dl(11.1 mmol/l)
2. ( )
mg/dl
(fasting plasma glucose:FPG)
3. (2-hPG) (oral glucose tolerance test: OGTT)

mg/dl ()
- OGTT (Specificity) (Sensitivity)

- FPG OGTT

plasma glucose

Diabetes
Diabetes
0

Mellitus

IGT
(pre-DM)

0
IFG

Mellitus

Normal

Normal
FPG

2h- PPG

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IFG = Impaired fasting glucose

IGT = Impaired glucose tolerance

233

3
Diabetic ketoacidosis (DKA) Hyperosmolar
hypergkyceneic state (HHS)
Pre-Diabetes

1. Impaired fasting glucose (IFG) Plasma 8

(FPG) (FPG < 100 mg/dl) (FPG 126 mg/dl)
IFG = FPG 100-125 mg/dl
2. Impaired Glucose Tolerance (IGT) Plasma
75 g. 2 (2-h Plasma glucose) (2-h PG < 140
mg/dl) (2-h PG 200 mg/dl)
IGT = 2-h PG 140-199 mg/dl
Plasma

Pre-diabetes
artherosclerosis complication
pre-diabetis

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.
.
.
. A1C

American Diabetes Association (ADA) American

Association of Clinic Endocrinologists (AACE)

paramitor

ADA

AACE

<80 or >140

<100 or >160
>

Mean FPG (mg/dl)

< 100
70 130
<110
Mean postprandial PG (mg/dl)
< 140
<180
<140
Bedtime glucose (mg/dl)
< 110
100 140
A1C (%)
<6
<7**
6.5
** <
Goal of therapy

(cardiovascular system) (coronary heartdisease; CHD)

Fasting plasma glucose (FPG)
Postprandial glucose (PPG)
A1C
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides
male (BMI)
female
Blood pressure (BP)

80-120 mg/dl
80-160 mg/dl
<7%
<200 mg/dl
<100 mg/dl
>45 mg/dl
<150 mg/dl
20-25 kg/m2
19-24 kg/m2
130/85 mmHg

>140 mg/dl
>180 mg/dl
>8%
>250 mg/dl
>130 mg/dl
<35 mg/dl
>400 mg/dl
>27 kg/ m2
>26 kg/m2
>160/95 mmHg

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(The Endocrine Society of Thailand)


()
Hemoglobin A1C
A1C (meanplasma
glucose; MPG) (pre- and post-meal glucose)
A1C A1C 1%
(microvascular complications) 35-40% A1C
<7% ( 6%) PPG <180 mg/dl A1C

(Life-style modifications)




1.

- (cholesterol
) - - > CHO: protein: lipid = 50-55%: 15-20%: <30%
-
-
saccharin, aspartame, cyclamate, acesulfame-K
- 2 1 - - >360
ml of beer , 100 ml of wine , 30 ml of whisky
-
2.
insulin

2 1
hypoglycemia (intensity)
(frequency) (duration) 30 3
(warm up) (cool down)

1.
A1c 1-2%
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236

2.
3.
4.
5.
6.
7.
8.

cholesterol TG,LDL

Drug class
. insulin
(Insulin secretagogues)
- Sulfonylurea (SU)
- Non-Sulfonylurea (NSU)
DPP-4
- DPP-4 inhibitor
.
insulin (Insulin sensitizers)
- Biguanides
- Thiazolidinedione(TZD)

-glucosidase Inhibitor

Mechanism of action

Primary site of action

Metabolis
m

Insulin release

Pancreas

Hepatic

Hepatic glucose product

Insulin sensitive

Carbohydrate absorption

Liver,Peripheral tissue

Sulfonylurea: SU
First generation :

Tolbutamide
Chlorpropamide
Second generation : Glibenclamide
Gliclazide
Glipizide
Glimepiride

Potency,Pharmacokinetics,
Safety first gen.

MCQ by MUPY RX39

NO/YES

Yes
Hepatic
No

Peripheral tissue,Liver

Small intestines

Real excreate
of active
metabolite

Intestinal

Yes

237

Machanism Of Action
insulin SU SUR(sulfonylurea receptor) cell ATP-dependent K+ channel
K+ depolarize Ca + channel Ca +
Ca + insulin

SAR
SU acidic functional group(sulfonylurea) aromatic ring
alkyl group
Duration

Activity

O
O
R1

N
H

N
H

R2

Toxicity

Nitrogen sulfonyl carboyl acidic proton hydrogen nitrogen

sulfonyl carboyl nitrogen hydrogen nitrogen

R

R = alkyl gr.
= Short duration
R = acetyl gr.
= Intermediat duration
R = halogen gr. = Long duration

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first gen Short-acting duration methyl gr. aromatic ring

inactive carboxylic acid metabolite - Chlopropamide Cl
aromatic ring second gen
R alkyl gr.
C3-C7 saturated ring
(weak acid) (hydrophobic) Chlopropamide
(hydrophilic)

sulfa sulfonamide
sulfa R4 H
SU R4 H

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1.
Type 2 DM
. response FBS < 240 mg/dl
3.
.

* active metabolite

Tolbutamide
Chlorpropamide
Glibenclamide**
Glipizide**
Glicazide**
Glimepiride

Orinase
Diabinese
Daonil
Minidiab
Diamicron
Amaryl

(mg)

time to
peak (hr)

duration
(hr.)

(mg.)

,
,
. ,.,
,

6-10
24-72
20-24
12-24
10-15
24

500-3000
125-500
2.5-30
2.5-30
40-320
1-6

,,

**
gen lipophilic gr.( Glibenclamide, Glipizide, Glimepiride)

/
2-3
1
1-2
1-2
1-2
1

100%
100%*
50%*
85%
60-70%
60%

gen entero-hepatic circulation

* NICE Guidline
1. Gliclazide : half life hypoglycemia
2. Glybenclamide : hypoglycemia

3. Glimepiride : second choice hypoglycemia

- phase 1
- dose -

- dose

hypoglycemia Glipizide = gliclazide <

glibenclamide
- second generatio

- sulfonylurea FPG -70 mg/dl A1C . - %

- Metformin
-
-
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-
-
Side effect
- Hypoglycemia
- 30

beta-adrenergicantagonist sulfonylureas betaadrenergic antagonist 15 g
- Weight gain
- hemolytic anemia
cholestasis

- sulfonylurea sulfa
- /(),
-
- Pancreatic diabetes
- ketoacidosis,hyperosmolar hyperglycemic coma severe hyperglycemia
- (teratogenicity)
(neonatal hypoglycemia) glibenclamide

-
Drug interaction hypoglycemia
- SU albumin : aspirin, fibrates, trimethoprim
- metabolism SU: H -blockers, anticoagulants, alcohol
- SU: probenecid,allopurinol
- sulfonylureas
calcium channel blockers, estrogen,
isoniazid, niacin, oral contraceptives phenytoin sulfonylureas
azole antifungals histamine-2 receptor
sulfonylureas
sulfonylureas sulfonylureas sulfonylureas

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sulfonylureas

- Chlorpropamide Glibenclamide
- Chlorpropamide Glibenclamide active metabolite
- half-life inactive
- Chlorpropamide (hyponatremia) ADH
(antidiuretic hormone)
(antabuse effect- disulfuram)
- glipizide glibenclamide

Non-sulfonylurea
Repaglinide(Novonorm), Nateglinide
Machanism of Action
insulin beta cells SU SUR
SU ( SU)

SU

(postprandial hyperglycemia)
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SAR
carboxylic acid SU

insulin

hypoglycemia

Onset
(min)

Duration
(hr)

(mg)

(.)

Repaglinide

Novonorm

15-30

4-6

.,,

0.5-4

2-3

Nateglinide

Starix

20

60-120

2-3

Pharmacokinetics
non-sulfonylurea secretagogues sulfonylureas
nateglinide > repaglinide > glipizide, glimepiride, gliclazide >tolbutamide,
glibenclamide (micronized formulation) > chlorpropamide, glibenclamide (nonmicronizedformulation)

SU
Side effect
hypoglycemia ,

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243

Type 1 diabetes mellitus
diabetes ketoacidosis
(Cat :C )
12

CYP 3A4
Drug Interaction
Repaglinide CYP450 3A4
Nateglinide CYP450 2C9, 3A4( In Vitro )
Gemfibrozil Repaglinide hypoglycemia

Biguanides
Metformin(Glucophage)
Machanism of Action
(decrease glycogenolysis decrease gluconeogenesis)
GLUT- [insulin-stimulated glucose transport in muscle cell]

glucose

SAR

guanidine 2

(BMI >25)

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Pharmacokinetics
half-life reservoir

Bioavailability 50-60%
plasma proteins
hepatic metabolism

Time to peak
(hr)

(mg)

(.)

Metformin

Glucophage

500,850,1000

500-2500

2-3

- 500 mg -
- - - ( SU
)
- .

FPG -70mg/dl
A1C .5- %
LDL triglyceride 10- %
HDL

-
anorexia
hypoglycemia
Side effect
(metalic taste)
B12 B12

(Lactic acidosis)

Lactic acidosis ()

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serum creatinine
Scr > 1.5 mg/dL, Scr > 1.4 mg/dL
lactic acidosis
( cat : B )
Drug Interaction

- cimetidine metformin cimetidine

metformin

- estrogen , corticosteroid , INH , nicotinic acid ,phenytoin , thiazide , thyroid\

Thiazolidinedione (TZD)
Rosiglitazone(Avandia),Pioglitazone(Actos)

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Machanism of Action
PPARv- (peroxisome proliferators-activated receptor-) insulin-responsive genes
carbohydrate lipid metabolism
insulin resistance
free fatty acid
adinopectin
SAR
- thiazolidine-2,4-dione
side chain
thiazolidine-2,4-dione

1.
Thiazolidinedione
2.
Methyl
3.
Phenyl
4.
O

2
2 Metformin
metformin
sulfonylurea
metformin 2
Pharmacokinetics

plasma protein 99%

1-2

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247

Time to peak
(hr)

Duration
(wk)

(mg)

(.)

Rosiglitazone

Avandia

1-2

>3-4

2,4,8

4-8

Pioglitazone

Actos

1-2

>3-4

15,30,45

15-45

-
-
- - ( )
- FPG 5-7
- ( ALT) ALT
- Monitor ALT (ALT)
- renal insufficiency

- Thiazolidinedione FPG -70 mg/dl

- A1C . - . %
- Pioglitazone triglyceride PPAR- rosiglitazone
- HDL , TG


SU metformin
SU / metformin
Side effect
. prostaglandin
-
- 2-4 kg.
- Anemia
2. 2 1
3. hypoglycemia
4. Troglitazone metabolite quinine
monitor troglitazone

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. NYHA (New York Heart Association) congestive HF class III IV ( Europe class)
.
.
. . -
. Congestive HF US FDA black box warning HF
6. Type 1 diabetes mellitus
7. diabetis ketoacidosis

- 4
-
- HF volume overload acute
exacerbation of heart failure
-
-
Drug Interaction
- rosiglitazone pioglitazone
CYP450 2C8 2C9 gemfibrozil
-glucosidase Inhibitor (AGI)
Acarbose(Glucobay), Voglibose(basen)
Machanism of Action
-glucosidase -glucosidase
oligosaccharide
monosaccharide (postprandial glucose)

acarbose -amylase polysaccharide oligosaccharide

SAR
acarbose carbohydrate like polymer miglitol voglibose
polyhydroxylated cyclohexane

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249

.

.
SU metformin
.

.
1
5.

Pharmacokinetics
2%
1
51% 96

(mg)

(.)

Acarbose

Glucobay

25,50,100

25-100

Voglibose

Basen

0.2,0.3

15-45

GI side effect

FPG -20 mg/dl A1C . - %

1.
postprandial hyperglycemia
2.
SU metformin 25-30 mg/dL
3.

Side effect
.

.

3.

.
, bowel obstruction
.

3.

4.

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Potency
GI side effect

Drug Interaction

- glucosidase digoxin

antacid, bile acid resin, activated charcoal, digestive enzyme efficacy- glucosidase

corticosteroid

SU*
NSU
Metformin
TZD
AGI

time to peak(hr)
2-6
1
2-3
1-2
1-2

half life(hr)
5-10
4-6
1-5
3-7
2

duration
12-24
4-6 hr
>3-4 wk
>3-4 wk
4 hr

*Second generation

SU
NSU
Metformin

FPG HbA 1c

LDL
(.%)
(%)

60-70
1.5-2

60-70
1.5-2

60-70
1.5-2

- %
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HDL

Triglyceride

- %

251

TZD
AGI

60-70

0.9-1.6

16-20

0.5-1

Insulin
(-cells)
A B disulfide
bridge (S-S)
- 2



1st phase
Plasma
Insulin
mg/dl

80
2nd phase

60
40
20

.

.

.

Insulin
Insulin preparation
Rapid acting
- Lispro
- aspart
Short acting
- Regular
Intermediate acting
- NPH (isophane)
- Lente ( zinc )

15

30

45

60

75

Time (min)

trade names

onset of
action

peak of
action

Humalog
Novorapid

15-30min
15-30 min

1-2 hr
1-2 hr

3-4 hr

ActrapidHM,HumulinR

30-60 min

2-3 hr

3-6 hr

HumalinN,InsulatardHM
Monotard HM

2-4 hr
3-4 hr

4-6 hr
6-12 hr

8-12 hr
12-18 hr

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effect duration

252

Long acting
- Ultralente
- Glargine
- Detemir
Combinations
-NPH/Regular

Ultratard HM
Lantus

6-10 hr
4-5 hr
2 hr

10-16 hr
No peak
6-9 hr

18-24 hr
22-24 hr
14-24 hr

Mixtard
Humulin80/20,70/30,

30-60 min

10-16 hr

Rapid acting
Lispro (Humalog) amino acid carboxy terminal B chain 29
proline lysine hexamer monomer

Aspart (Novolog) recombinant DNA aspart proline
Lispro
Short acting
Regular (Humarin R,Actrapid HM)

Intermediate acting
NPH [neutral protamine hagedorn insulin](Humalin N,Monotard) isophane insulin
protamine -
Lente insulin zinc
Slow acting
Glargine arginine 2 carboxy terminal B chain Isoelectric point pH 5.4
. asparagines glycine A chain analog

basal insulin
- Detemir treoninem B 30 myristic acid
albumin
Combinations
-

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Type 1 ( : / )
0.5-0.6
Honeymoon phase(
1
) 0.1-1.4
Split-dose therapy 0.5-1.2
With ketosis or during acute illness 0.5-1.0

Type 2 ( : / )
0.2-0.6
Split-dose therapy 0.5-1.2
With insulin resistance 0.7-2.5

1. [intermediate-acting insulin]

2. insulin mixture
3. 2 [intermediate-acting insulin]
2/3 1/3
4. insulin mixture hr
5. 3-4 [multiple injection] Regular insulin 3 Long-Acting Insulin

6. continuous subcutaneous infusion pump regular insulin

10-20 /
0.6 /../
3-7 2

1.
2. Sc
3. Pump
( basal line
)
4. Inhalation: Exubera inhaled insulin (dry powder inhalers; DPI)

.

.
.

.
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254

Side effect:
.
2. Lipodystrophy
.
.
aqueous humor
.


U100 1 cc. 100
10 cc. 1000
2-8 C 30 1

Incretin Mediated Therapy

Incretin hormone
2
peptide 2
glucose-dependent insulinotropic polypeptide gastric inhibitory polypeptide (GIP)
glucagon-like peptide-1 (GLP-1) 30-amino acid peptide glucagon 50% L cell
dipeptidyl peptidase IV (DPP-IV)
GLP-1

1.
2.
3.
4.

1.
2. ()

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Glucagon-like peptide- Receptor agonist (GLP-1)

Exendin-4; potent GLP-1 agonists
- Gila monster DPP-4
Exenatide(Byetta); synthetic exendin-4
- Gila monster
-

GLP-1 GLP-1 Receptor

GLP-1 DPP-IV glycine
-
mcg/ml mcg
mcg
- metformin, sulfonylurea, TZDs combination

-
Exenatide-LAR ; sustained-release Exenatide
-
Liraglutide ( Victoza); fatty acylated human GLP-1
- DPP-IV Albumin
- 11-15 h

Dipeptidyl peptidase IV Inhibitor (DPP-IV Inhibitor)

Sitagliptin (Januvia) ,Vildagliptin (Galvus), Saxgliptin (Onglyza)
DPP-IV Incretin hormone ( GLP- )
2
GI side effects, GLP-1agonist
Sitagliptin (Januvia )
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256

- Dose = 100 mg orally once daily

- combine
-
o Dose = 50 mg (creatinineclearance 3050 mL/min)
o Dose = 25 mg (creatinine clearance <30 mL/min).
Vildagliptin (Galvus)
- combine Vildagliptin 100 mg/d
o Dose = 50 mg orally twice daily metformin thiazolidinedione
o Dose = 50 mg orally once daily sulfonylurea
- dizziness, headache, peripheral oedema, constipation, nasopharyngitis, upper respiratorytract
infection, and arthralgia.
- hepatic impairment
- 3
- ALT, AST 3
GLP-1agonistDPP-IV Inhibitor receptor ATP glucose
receptor hypoglycemia

Pramlintide(Symlin)
human amylin -cell

HbA1c
ml 1
2 insulin therapy
1; mcg mcg -60 mcg
;
mcg max dose 120 mcg
:nausea and vomiting, anorexia, headache.

- insulin hypoglycemia 3 hrs pramlintide

- 1 hypoglycemia short-acting or rapidacting insulin initial dose pramlintide 50%

SGLT2 Inhibitors
Phlorizin, Dapaglizin, Sergliflozin, Remogliflozin
SGLT2 Inhibitors
Type 2 diabetes
SGLT2 transporter
- transporter early proximal tubule
- reabsorption %
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- affinity
- gene mutation transporter (renal glucosuria)

Mechanism of Action
- SGLT2 transporter
- reabsorp
-

-
- ()

Dose-dependent effect
-
-
-
-
Side effects
1.

2.
3.
4. Hypoglycemia ()
5.
6.
7. Hematocrit
8.
*side effect HTN, obesity

SGLT2 inhibitors
- insulin glucose metabolism hypoglycemia
-
-
- Side effects
- Mild osmotic diuretic CHF

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( 2554)

Algorithm for the metabolic management of type 2 diabetes

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Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check
A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C
is 7%. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. Insufficient clinical use to be
confident regarding safety.

Complications

Acute complication
1. Hypoglycemia
2. Hyperosmolar coma shock
3. Diabetic ketoacidosis


Chronic complication

(coronary heart disease: CHD)

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Total cholesterol (./.)
LDL-cholesterol (./.)

Fasting triglycerides (./.)

<170
<100
>40
>50()
<150

Body mass index (./ )

18.5-22.9

<90
<80

HDL-cholesterol (./.)

<130/80

*
LDL-cholesterol 70(./.)
** 140-110/70
Ref : .2554
ACEI (angiotensin-converting enzyme
inhibitors) ARBs
Statin CHD CHD
aspirin 75-162 mg/d A1C %
- %







1. Microvascular: retinopathy (glaucoma,cataract), nephropathy,neuropathy
FPG
2. Macrovascular; cerebrovascular disease, CHD, peripheral vascular disease
(
FPG>100)
Microvascular
Retinopathy



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Treatment
1.
2. A1C < %
3.
-
-
Nephropathy


Microalbuminuria Macroalbuminuria
Treatment
1. ACEI(angiotensin-converting enzyme inhibitors) ARBs
ACEI Microalbuminuria ARBs
Macroalbuminuria
2. A1C < %
3. albumin
4. albumin

- -
-
Neuropathy

1. Peripheral neuropathy:

Amputation
Treatment: hyperglycemia, hypertension, dyslipidemia
: tricyclic antidepressants,Anti-convulsant
:
2. Autonomic neuropathy
- Cardiovascular: (> bpm), Orthostasis hypotension
- GIAutonomic neuropathy:
- Genitourinary:

UTI
- Sexual: Erectile dysfunction and/or Retrograde ejaculation
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Macrovascular
Cardiovascular disease Stroke
Cardiac disease: AMI,Ischaemia

1.

2.

3. ()
-

-

-
4.
5. , ,
, ,

cotton or wool

3-6



()

()

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6.


7.

8. ,

9.

Reference
1. Nature publishing group. Pharmacotherapy for the Treatment of Patients with
Type 2 Diabetes Mellitus: Rationale and Specific Agents. CLINICAL PHARMACOLOGY & THERAPEUTICS 2007;
81(5):636-649.
2. . 2.
; : - .
3. , ,.Inhaled Insulin: Exubera.Thai Pharm Health Sci J
2006;1(2):170-179
4. .

5. Kumar A,Nair R,Jagadish V,Oral hypoglycemic agents for treatment of type II Diabetes Mellitus
: A Review.
6. ADA recommended algorithm. Nathan DM et al. Diabetes Care. 2006;29:19631972 [19].
7. Matindale
8. Goodmangrillman
9. Pco tx handbook
10.
11. : . .
12. 2554 ,
13 .Medical Management of Hyperglycemia in Type 2 Diabetes : the American Diabetes Association and the
European
Association for the Study of Diabetes ; Diabetes Care. 2009 January; 32(1): 193203.

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Hormone Replacement Therapy

. 5003096
. 5003045
.
5103029

** !!

1
Menopause ()
(WHO)
(Menopause)
1. Natural menopause 12 ( 1
)
49-51
1.5
2. Surgical menopause

3. Premenopause
3 40
4. Perimenopause () 4-5
1
5. Postmenopause Natural Surgical menopause
6. Climacteric period Premenopause, Perimenopause Postmenopause
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(
)

(Pathology of Menopausal symptom)

Hypothalamic-pituitary-ovarian axis (HPO axis)
Hypothalamus GnRH pituitary FSH LH
FSH : follicles granulosa theca cell follicle estradiol
(E2) (follicular phase) progesterone (luteal phase)
LH :
Menopause follicles FSH
estradiol feed back pituitary FSH LH follicle
FSH estradiol FSH
LH estradiol (E2) (Menopausal symptom) follicles
FSH estradiol estrogen
estrone (E1) androgen estrone androgen

, Management of Common Menstrual

estrogen estrogen
estrogen androgen
estrogen estrogen

Estradiol (estradiol-17 E2) estrone (E1) estrogen
- (Reproductive age) estrogen estradiol (estradiol-17 E2)
- (Menopause) estrogen estrone (E1)

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(Menopausal symptom Climacteric syndrome)

(Menopause) hypothalamicpituitary-ovarian axis FSH LH estrogen estrogen

(Short term)
1. Neuroendocrine system
1.1 Vasomotor symptoms (2 menopausal
symptoms) hot flushes hot flashes
1.2 Psychosexual symptom

2. Urogenital system
receptor estrogen
estrogen menopause (atrophy)

(vaginismus)
(dyspareunia) (uterovaginal prolapse)
(cystocele)

(urethral infections) (dysuria)

3. Skin and mucous membrane symptoms

4. musculo-skeletal system
(climacteric arthralgia)
5. Cup of the breast

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(Long term)
Osteoporosis & bone fracture
estrogen bone formation osteoblast ( )
bone resorption osteoclast ()
(bone mass) bone mineral density (BMD) BMD . SD
osteoporosis

Hormone
12 menopausal syndrome


estrogen


perimenopause
menopausal symptoms Hormone replacement therapy (HRT)
1. (Serum hormone levels)

FSH < 40 mIU/ml

LH > 25mIU/ml
LH: FSH ratio < 0.7
E2 10-20 pg/ml
FSH E2
FSH LH
2. Vaginal hormonal cytology
Smear (lateral vaginal wall) mucus
smear 1% pinacyanol ( ) 1-2
slide cell
- estrogen superficial cell 15-30% intermediate cells
-
estrogen (hypoestrogenic state) parabasal cell 50%
3. Fern pattern
(cervical mucus) smear slide
estrogen Vaginal hormonal cytology Fern
pattern

Treatment
1.


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hot flushes
-
-
-
estrogen (phytoestrogen) ** **
hot flushes
Common ADR phytoestrogen
- Constipation
- Bloating
- Nausea
Vitamin E vitamin E 900 IU hot flushes
Antidepressants Venlafaxine , Paroxetine , Fluoxetine
endorphine
5

2.
2.1 Estrogens (Estrogen replacement therapy ERT)
menopausal symptoms

osteoporosis
estrogen proliferation
(endometrial) endometrial cancer ( ** estrogen
Conjugated estrogen(Premarin) 0.625-1.25 mg/day** ( ) cyclic
continuous
combined HRT progestogens
breast cancer)
conjugated estrogens (Premarin) 0.3 mg 17 -estradiol (Estrofem)
0.5 mg
estrogen

** Transdermal patch first pass metabolism **

side effect estrogens (*Conjugated estrogen(Premarin) 0.625-1.25 mg/day*)
** Venous Thromboembolism ** :
:
: Estrogens/
estrogens
1.
- conjugated estrogens (Premarin)
-17 -estradiol (Estrofem)

osteoporosis
0.625 mg
1-2 mg

Vasomotor Symptoms
Mild
Moderate & Severe
0.625 mg

1.25 mg
2-4 mg

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- estradiol valerate (Progynova)

- ethinyl estradiol (Progynon C)
- estriol (Ovestin)
2.
2.1Transdermal patch
** first pass metabolism **
-17beta-estradiol patch (Estraderm)
2.2Percutaneous
-17beta-estradiol gel
(Estrogel0.05% cream)
3.( implant subcutaneous )
- 17beta-estradiol pellet(Estrapel)
4.
4.1 Vaginal ring : 17beta-estradiol
4.2 Vaginal tablet : 17beta-estradiol
(Vagifem)

2-4 mg
5-20 g
2-8 mg

1-2 mg

1 mg

50 g

50 g

100 g

25 g

25-50 mg

50-100 mg

25 mg

1.5 mg

25-50 mg
5-10 mg

25 g

2.2 Estrogens + Progestogens

( estrogens progestogens )
progestogens proliferation
(endometrial) **progestogens endometrial cancer**
progestogens 10
progestogens estrogens

Types of Cyclic HRT

1. Cyclic sequential combined
E&P
( 21 11 E
10 E&P

7 )

- Prempak
(conjugated estrogen 0.625 mg 21
+ medrogestone 5 mg 10 )
- Cyclo-Progynova
(estradiol valerate 2mg 21 +
norgestrel 0.5 mg10)
- Climen
(estradiol valerate 2mg 21 +
cyproterone cetate1 mg10)

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347

2. Cyclic sequential combined E,

A&P ( E&A 25
P 13-25
3
)
3. Cyclic unopposed E
( E 21 7
E )

- ERT
- 7

-
-

Estrogens + Progestogens 2
2.2.1. Cyclic hormone replacement therapy Perimenopause
3 (E Estrogen, P Progestogen, A Androgen dose mg /
2.2.1 )
2.2.2 Continuous hormone replacement therapy Postmenopause 6

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2.2.1. cyclic hormone replacement therapy

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2.2.2 Continuous hormone replacement therapy Postmenopause 6

2.2.2 Continuous hormone replacement therapy

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HRT: HRT
1.
2. ,
(severeoligo-amenorrhea)
- Turners syndrome
- Anorexia nervosa ()

3.
(premature menopause)
4. (bone mass) 1 SD peak bone mass
5.
osteoporosis
Types of Continuous HRT
1.Continuous unopposed E
( E
)

2.Continuous combined E&P

( 28 E&P

)
3.Continuous sequential
combined E&P
( 2.2 P
10-14 )
4.Continuous triphasic
sequential combined E&P
( 28 12 E
10 E&P
6 E

)
5.Continuous estrogen with
intermittent progestogens
( E P
3
3 )
6.Continuous combined E,
A,P 28 E, A,P

-Kliogest
(1 17-estradiol
2mg+norethisterone acetate 1
mg)

- ERT
-
menopausal symptoms

-Trisequens
(estradiol 2 mg 12 ,
Estradiol 2 mg+norethisterone
acetate 1 mg 10 ,
Estradiol 1 mg 6 )

- P

-Livial
(1 tibolone 2.5
mg tibolone
E,P,A)
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HRT
1. (hot flushes)
estrogen
80 3
2. urogenital symptoms
estrogen
(atrophic vaginitis) estrogen ,

3. Osteoporosis & bone fracture
estrogen
-
osteoclast activity cytokines & other bone affecting agent
- calcium
Ca2+absorption, renalCa2+excretion,PTH(parathyroid hormone) secretion,
calcitonin secretion
BMD bone fracture
( HRT treatment of choice osteoporosis
bisphosphonate estrogen
)
Calcitonin

PTH

4. colorectal cancer
estrogen estrogen
bile acid bile acid
estrogen estrogen receptor proliferation colorectal cancer
cell apoptosis cancer cell
5. endometrial cancer
** progestogen estrogen endometrial cancer **

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HRT :
1. Coronary heart disease
conjugated equine estrogen (CEE) 0.625 . CEE 0.625 . +
Medroxyprogesterone acetate (MPA) 2.5 . atherosclerosis
coronary (coronary heart disease)

2. Stroke
WHI (2002) (Womens Health Initiative study) WHI (2004) estrogen +
progesterone estrogen stroke
3. * *Venous thromboembolism (VTE) **
estrogen estrogen+progesterone
venous thromboembolism
venous thromboembolism


4. Breast cancer
estrogen ductal epithelium meiotic activity
cells ducts connective tissue
sex hormone breast cancer

5. Ovarian cancer
estrogen 1.6 16 estrogen +
progestogen 1.1 11
9 Charla M.
Blacker, MD, FACOG Prevention and Treatment of Osteoporosis estrogen
(www.glowm.com) estrogen
estrogen+progestogen
6. Cognition & dementia
estrogen progestorone
dementia 65

7. Gallstone disease
estrogen
super saturated with cholesterol
cholesterol stone
cholecystectomy
gallbladder stone
% Oral CEE 2% Transdermal 1.3%

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HRT

1. (hot flushes)
2. Urogenital symptoms
3. Osteoporosis
& fracture
4.
Colorectal cancer
5.
Endometrial cancer

1.Coronary heart disease

2. Stroke
3. **Venous thromboembolism**
4. Breast cancer
5. Ovarian cancer
6. Cognition & dementia
7. Gallstone disease

Contraindication of Estrogens
1. (breast cancer)
estrogens proliferation Tamoxifen
( anti-estrogen estrogen tissue )
2. (endometrial cancer)
estrogens proliferation (endometrial)
endometrial cancer
estrogens
3. Severe liver dysfunction
metabolize estrogens
progestogens metabolize 2
4. Porphyria ( ) enzyme hemoglobin estrogen HRT
enzyme
5. Abnormal vaginal bleeding ()
6.

Contraindication of Progestogens
Meningioma : progesterone receptors progestogens
antiprogestogen

menopausal syndromes
hot flushes Estrogen
dose (Transdermal patch) dose
( )

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(perimenopause) (early
postmenopause) estrogen
estrogen

Selective Estrogen Receptor Modulators (SERMs)

estrogen agonist estrogen receptor
estrogen antagonist
Tamoxifen, Raloxifen

lasofoxifene, bezedoxifene arzoxifene

Tamoxifen

Raloxifene
(Celvista, Evista 6omg/tab Dose: 60 mg/day)

(Nolvadex 10mg/tab, Nolvadex-D 20mg/tab

Dose: 20-40 mg/day)

Preg. Cat.: D
SERMs 1gen

Benzothiophene derivative
Preg. Cat.: X
SERMs 2gen

Indication

Indication

Estrogen antagonist


Estrogen agonist ,
Lipid profile cholesterol metabolism

total cholesterol (TC) LDLcholesterol

Estrogen agonist , Lipid profile

cholesterol metabolism
estrogen antagonist hypothalamus

hyperplasia
total cholesterol LDL-cholesterol


Tamoxifen

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S/E: - Fluid retention

- Depression
- Skin changes
- Hot flashes
- Vaginal bleeding
-
-

S/E: - venous thromboembolic event

- hot flushes
- pulmonary embolism
- leg cramps
- peripheral edema
- deep vein thrombosis
- retinal vein thrombosis
- cognitive function
-
Tamoxifen

Selective Tissue Estrogenic Activity Regulator (STEAR)

Tibolone (Livial Dose: 2.5 mg/day)
- -nortestosterone derivative
- Weak estrogenic, progestagenic androgenic properties

Indication
- osteoporosis
- hot flushes vasomotor, psychological, and libido problems

- S/E: weight gain, dizziness, vaginal symtom, GI upset

- 1 (
bleeding)
- estrogen-only HRT combined HRT
-
- muscle strength, lean body mass , total body fat content

Comparison of selected actions and side effects of estrogen, SERMs and STEAR
Side Effects
Estrogen Tamoxifen Raloxifene Tibolone
Hot flushes
Uterine bleeding
Risk of endometrial cancer
Prevention of postmenopausal bone
loss
Risk of breast cancer
Favorable pattern of serum lipids
Venous thrombosis

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Reference
1.
, , .
. : - () , 2539
2. , . Menopause -
. 10700,
http://www.sirirajmedj.com/content.php?content_id=
3. , . . : , 2543.
4. , , , . . :
, 2548
5. ... , . . : ,
2545 . Hormone Replacement Therapy

6. . , . . :
.., 2551

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