This document provides an overview of endocrine hormones and their functions. It begins with definitions and classifications of hormones, then discusses hormone secretion, transport, clearance, and mechanisms of action. Specific hormones discussed include growth hormone, thyroid hormones, parathyroid hormone, calcitonin, calcium and phosphate metabolism, vitamin D, insulin, estrogen, and others. The document explains hormone synthesis, storage, release, feedback loops, and transport. It also covers hormone receptor activation and second messenger mechanisms. In summary, the document provides a comprehensive introduction to endocrinology and the roles of various hormones in regulating physiological processes.

1. Presented by :
Mayank Khandelwal
1st year post graduate student
Dept of orthodontics & dentofacial
orthopaedics

2.  Introduction
 Classification
 Hormone secretion
 Hormone transport
 Clearance of hormones
 Mechanism of action of hormones
 Hormone receptor and activation
 2nd messenger mechanism
 Growth hormone
 Thyroid hormone
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 Parathyroid hormone
 Calcitonin
 Calcium and phosphate metabolism
 Vitamin D
 Insulin
 Estrogen
 Conclusion
 References

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 The multiple activities of the cells, tissues, and organs of the body are
coordinated by the interplay of several types of chemical messenger
systems.
Neurotransmitters
Endocrine
hormones
Neuroendocrine
hormones
Paracrines Autocrines Cytokines

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 Definition –
Substances produced by highly specialized tissues called “endocrine
glands”, carried by the blood stream to a remote tissue or viscera called the
“target organ” on which they exert their physiological effects
 The multiple hormone systems play a key role in regulating almost all
body functions, including metabolism, growth and development, water
and electrolyte balance, reproduction, and behaviour.
 Eg. Without growth hormone : Dwarfism
 Without thyroid hormone : Person will be sluggish

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 ENDOCRINE GLANDS :
• Luteinizing hormone
• Follicular stimulating hormone
• Prolactin
• Adrenocorticotropic hormone
• Growth hormone
• Thyroid stimulating hormone
Anterior pituitary
• Antidiuretic hormone
• Oxytocin
Posterior pituitary
• Corticotropin releasing hormone
• Gonadotropin releasing hormone
• Growth hormone releasing hormone
• Prolactin releasing hormone
• Thyrotropin releasing hormone
Hypothalamus

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• Thyroxine (T4)
• Tri-iodothyronine (T3)
• Calcitonin
Thyroid gland
• Parathyroid hormoneParathyroid gland
• Insulin
• Glucagon
Pancreas
• Aldosterone
• Cortisol
Adrenal cortex
• Catecholamines (Epinephrine and
Norepinephrine)
Adrenal medulla
• Testes (Testosterone and dihydrotestosterone
• Ovaries (Estrogens including estradiol and
estrone)
Gonads

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 Based on nature of action :
 General Hormones: Influences nearly all the body tissues
Growth hormone, thyroid and insulin hormones
 Specific Hormones: These hormones affect functions of specific organs
e.g. FSH and androgens.
 Local Hormones: Prostaglandins, Acetyl choline, Histamine act locally
to their site of production.

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 Based on the chemical structure :
 Proteins and polypeptides
 Hormones of anterior and posterior pituitary gland, the pancreas
(insulin and glucagon), parathyroid gland (parathyroid hormone), etc.
 Steroid hormones
 The adrenal cortex (cortisol and aldosterone), ovaries (estrogen and
progesterone), testes (testosterone), and placenta (estrogen and
progesterone)
 Derivatives of amino acid tyrosine
 Thyroid (thyroxine and triiodothyronine) and adrenal medullae
(epinephrine and norepinephrine).

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a. Protein and polypeptide hormones :
 Most of the hormones
 Size varies from 3 amino acids to 200 amino acids
 Synthesis : Rough end of the endoplasmic reticulum
Large proteins
which are not
biologically active
(pre-prohormones)
Prohormones in
endoplasmic
reticulum
Golgi apparatus for
packaging in
secretory vesicles
Prohormones
Small biologically
active hormones
and inactive
fragments
Vesicles bound to
cytoplasm and cell
membrane

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 How does synthesis occur ?
 It occurs when secretory vesicles fuse with cell membrane and granular
contents are extruded into interstitial fluid or blood stream directly
(exocytosis)
 Stimulus for exocytosis :
 1st : increase in cytosolic Ca2+ caused by depolarization of plasma
membrane
 2nd : Stimulation of endocrine cell surface receptor
Increased cyclic adenosine monophosphate {cAMP}
Activation of protein kinases
Initiates secretion of hormones

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b. Steroid hormones :
 Lipid soluble hormones
 Synthesized from cholesterol in most cases
 Structure :
 3 cyclohexyl rings and 1 cyclopentyl
ring combined into 1 structure
Steroids (highly lipid soluble)
Easy diffusion via cell membrane
Enters interstitial fluid
Enters circulation
Reaches target organ / tissue

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c. Amine hormones from tyrosine :
 2 groups are derived : Thyroid hormones
Adrenal medullary hormones
 THYROID HORMONES :
 Incorporated in thyroglobulin
 Storage : large follicles in thyroid gland
Thyroglobulin
Free
hormones
Released in
blood stream
After entering
blood stream
Combines with
plasma protein
(esp. thyroxine
binding globulin)
Slow release of
hormones to
target tissues
Amines
split

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 ADRENAL MEDULLARY HORMONES :
 Epinephrine and norepinephrine
 These are also stored in vesicles and stored until needed
 Release – exocytosis
 On entering circulation,
 Free form
 Conjugated with other substances

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 Onset of secretion
 After a stimulus, onset can range from a few seconds (eg. Epinephrine
and norepinephrine) to few months (eg. Thyroxine and growth
hormone)
 Each hormone has its own characteristic onset and duration of action
 Concentration of hormone in circulation
 It also varies from few picograms / ml of blood to few micrograms / ml
of blood

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 Feedback control mechanism
 Negative feedback
 Positive feedback
 Cyclic variation
 Negative feedback :
 Prevents over activity of the hormone
 Controlling variable – degree of target tissue activity
 Once target tissue activity reaches a specific level, negative feedback
mechanism is generated and secretion is terminated
Stimulus
Hormone
release
Negative
feedback
Stoppage
of
secretion
Preventio
n of over-
secretion

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 Occurs at all levels
 Gene transcription level
 Translational steps involving synthesis of hormones
 Steps in processing of hormones
 Release of stored hormones
 Positive feedback :
 Biological activity of hormone further enhances the secretion of the
hormones
 Eg. Lutenizing hormone (LH) surge due to stimulatory effect of
estrogen on anterior pituitary before ovulation
 Secretion of LH Acts on ovaries further secretion of
estrogen more secretion of LH
 Eventually, LH sends a negative feedback

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 Cyclic variation :
 Influenced by seasonal changes, various stages of development, age,
diurnal cycle, sleep, etc.
 E.g. Growth hormone secretion increases in early period of sleep
but reduces in late period of sleep
 It may be due to change in the activity of neural pathways involved in
controlling hormone secretion

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a) WATER SOLUBLE :
Dissolves in plasma and transported from synthesis site to target site
Diffuses out of capillaries to interstitial fluid
Reaches target cell
b) LIPID SOLUBLE :
Exist in 2 forms : free form (10%) and plasma protein bound (90%)
Since plasma protein bound hormones cannot diffuse across cell
membranes, they are inactive until they are dissociated from plasma
protein
Bound to protein acts as a reservoir
It slows the clearance of hormones

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 Depends on 2 factors : Rate of hormone secretion into blood
Rate of removal of hormone from blood (metabolic clearance rate)
 Pathways of hormone clearance :
Metabolic destruction by tissue
Binding with the tissue
Excretion by liver into bile
Excretion by kidney into urine
 Hormones are sometimes degraded at their target cells by enzymatic
processes that cause endocytosis of the cell membrane hormone-
receptor complex; the hormone is then metabolized in the cell, and the
receptors are usually recycled back to the cell membrane.

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 Peptide hormones :
 These are water soluble, hence circulate freely in the blood
 Degraded by the enzymes in blood and tissue and excreted by the
kidney
 Hence, these hormones have short duration in the blood
 Eg. Angiotensin II circulates in the blood for less than a minute
 Hormone bound to plasma proteins :
 Cleared at much slower rate
 May remain in the circulation for days
 Eg. Half life of adrenal steroids : 20-100 minutes
 Half life of protein bound thyroid hormones : 1-6 days

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 Hormone receptors and its activation :
 1st action : Binding of hormone to its receptors
 Cells without hormone receptors does not provide any response to the
hormones
 Hormone receptors: Protein in nature
 Each cell has about 2000-100000 receptors
 Each receptor : specific for a single hormone
 Location : In or on the surface of cell membrane
In the cell cytoplasm
In the cell nucleus

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 Number and sensitivity of receptors :
 It does not remain constant
 Receptor proteins are often inactivated or destroyed during the course
of their function, and at other times they are reactivated or new ones
are manufactured by the cell.
 Eg. increased hormone concentration and increased binding with its
target cell receptors sometimes cause the number of active receptors
to decrease resulting in down-regulation of the receptors
 The stimulating hormone induces greater than normal formation of
receptor or intracellular signalling molecules by the target cell or
greater availability of the receptor for interaction with the hormone i.e.
up-regulation of the receptors

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 Intra-cellular signalling after hormone receptor activation :
Ion channel linked
receptors
G-protein linked
hormone receptors
Enzyme linked
hormone receptors
Intra-cellular hormone
receptors and
activation of genes

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 Ion channel linked receptors :
 Neurotransmitters combine with receptors in post synaptic membrane
 Causes change in the structure of the receptor
 Opens or closes the channels for the ions
 Movement of ions causes subsequent changes

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 G-protein linked receptors :
 G-proteins coupled receptors have seven transmembrane segments
that loop in and out of the cell membrane.
 G proteins include three (i.e. trimeric) parts—the α, β, and γ subunits.

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Some hormones are coupled to inhibitory G proteins ( Gi proteins), whereas
others are coupled to stimulatory G proteins ( Gs proteins).

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 Enzyme linked receptors :
 Leptin is a hormone secreted
by fat cells and has many
physiological effects, but it is
especially important in
regulating appetite and
energy balance
 The leptin receptor is a
member of a large family of
cytokine receptors that do not
themselves contain
enzymatic activity but signal
through associated enzymes.
 Here, one of the signaling
pathways occurs through a
tyrosine kinase of the janus
kinase (JAK) family, JAK2.

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 Intra cellular hormone receptors :

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 SECOND MESSENGER MECHANISMS FOR MEDIATING
INTRACELLULAR HORMONAL FUNCTIONS :
 Hormones exert intra cellular actions by stimulation of 2nd messenger
which causes further actions
 2nd messengers used by hormones :
 cAMP
 Calcium ions and associated calmodulin
 Products of membrane phospholipid breakdown

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 Adenylyl Cyclase–cAMP Second Messenger System

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 The specific action that occurs in response
to increases or decreases of cAMP in each
type of target cell depends on the nature
of the intracellular machinery.
 Different cells have different enzymes.
Hence, different functions are elicited in
different target cells, such as initiating
synthesis of specific intracellular
chemicals, causing muscle contraction or
relaxation, initiating secretion by the cells,
and altering cell permeability.
 Thus, a thyroid cell stimulated by cAMP
forms the metabolic hormones thyroxine
and triiodothyronine, whereas the same
cAMP in an adrenocortical cell causes
secretion of the adrenocortical steroid
hormones.

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 Cell Membrane Phospholipid Second Messenger System
Phosphatidylinositol
biphosphate (PIP2)
Inositol triphosphate
(IP3)
Diacylglycerol (DAG)

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 Calcium-Calmodulin Second Messenger System :
 Calcium entry may be initiated by changes in membrane potential that
open calcium channels or a hormone interacting with membrane
receptors that open calcium channels.
 Calcium ions bind with the protein calmodulin
 Change in the shape of calmodulin
 Activation / inhibition of protein kinases
 Activation / inhibition of proteins involved in cell’s response to
hormones

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 Importance of 2nd messenger concept in orthodontics :
 The second-messenger hypothesis postulates that target cells respond
to external stimuli, chemical or physical, by enzymatic transformation
of certain membrane-bound and cytoplasmic molecules to derivatives
capable of promoting the phosphorylation of cascades of intracellular
enzymes.
 Therefore, increases in the tissue or cellular concentrations of second
messengers are generally viewed as evidence that an applied
extracellular first messenger, such as an orthodontic force, has
stimulated target cells.
 The literature includes many reports on significant elevations in the
concentrations of intracellular second messengers in paradental cells
after exposure to applied mechanical forces.

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 Hormones acting on genetic machinery of the cell :
 Steroid hormones increase protein synthesis

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 Thyroid hormones cause increased gene transcription in cell
nucleus
 Features of thyroid hormone function in the nucleus
1. Activate genetic mechanism for many intra-cellular proteins
which promote enhanced intra-cellular metabolic activity in
almost all cells of the body
2. Once bound to the intranuclear receptors, the thyroid
hormones can continue to express their control functions for
days or even weeks

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 BIOSYNTHESIS :
 Long arm of chromosome 17 has the growth hormone hCS gene cluster
containing 5 genes : hGH-N, hGH-V, 2 for hGH-M and hCS pseudogene
 PLASMA LEVELS AND BINDING :
 A portion of circulating growth hormone is bound to a plasma protein
that is a large fragment of the extracellular domain of the growth
hormone receptor
 Approximately 50% of the circulating pool of growth hormone activity
is in the bound form
 Half life of GH : 6-20 mins
 Daily output : 0.2 – 1 mg /day in adults

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 GH gets metabolized rapidly in the liver.
 GROWTH HORMONE RECEPTORS :
 620 amino acid protein with a large extra cellular portion, a trans
membrane domain and a large cytoplasmic portion
 It has 2 domains which can bind to the receptor producing a dimer
which is necessary for activation
 It gets activated by cytoplasmic tyrosine kinase pathway

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 Physiological functions of GH :
 Promotes growth of many body tissues
 Enhances amino acid transport through cell membranes
 Enhances RNA translation to cause protein synthesis
 Increases nuclear transcription from DNA to RNA
 Decreases catabolism of proteins and amino acids
 Metabolic effects
 Increased rate of protein synthesis
 Increased mobilization of fatty acids from adipose tissue and
increased use of fatty acids for energy
 Decreased rate of glucose utilization throughout the body
 The ability of growth hormone to promote fat utilization, together with
its protein anabolic effect, causes an increase in lean body mass

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 GH decreases carbohydrate utilization by decreased glucose uptake by
tissues, increased glucose production and increased insulin secretion
 GH stimulates bone and cartilage growth
 Increased deposition of protein by the chondrocytic and osteogenic
cells that cause bone growth
 Increased rate of reproduction of these cells
 A specific effect of converting chondrocytes into osteogenic cells,
thus causing deposition of new bone.
 2 pathways :
1. Long bones grow in length until the epiphyses are not fused when
stimulated by GH
2. Osteoblasts are strongly stimulated by GH resulting in more
deposition of the bone

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 SOMATOMEDINS :
 Growth hormone causes the liver and other tissues to form several
small proteins called somatomedins that have the potent effect of
increasing all aspects of bone growth.
 The somatomedins are also called insulin-like growth factors (IGFs).
 At least four somatomedins have been isolated, but the most important
of these is somatomedin C
 Somatomedins attach strongly to carrier protein hence released slowly
to blood and has increased duration of action.

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 REGULATION OF HORMONE SECRETION :
 It is secreted in pulsatile pattern
 Factors associated with nutrition which stimulates the secretion :
 Starvation
 Hypoglycemia
 Exercise
 Excitement
 Ghrelin

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 Growth hormone secretion is controlled by two factors secreted in the
hypothalamus and then transported to the anterior pituitary gland
through the hypothalamic-hypophyseal portal vessels.
 They are growth hormone–releasing hormone (GHRH) and growth
hormone inhibitory hormone (also called somatostatin)
 Most of the control of growth hormone secretion is probably mediated
through GHRH rather than through the inhibitory hormone somatostatin
 GHRH attaches itself to specific cell membrane receptors which activates
cAMP system
 Short term effects : increased calcium ion transport resulting in hormone
release into the blood
 Long term effects : increase transcription in the nucleus by the genes to
stimulate synthesis of new growth hormone.

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 FEEDBACK OF GROWTH HORMONE SECRETION :

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 Abnormalities of Growth Hormone secretion
 Panhypopituitarism
 Effects : Hypothyroidism
Depressed production of glucocorticoids
Suppressed secretion of gonadotropic hormones
 Dwarfism
 Gigantism
 Acromegaly

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 GROWTH HORMONE AND ORTHODONTICS :
 Dental development –
 Dentition seems to be harmoniously delayed, so that all studied
components of dental development (primary root resorption,
secondary tooth formation and eruptive movement) display the same
degree of retardation.
 GH influence on growth starts after 9 months of age, so that the
effect on the growth of primary teeth is very little known.
 GH DEFICIENCY :
 Children show big skull with babyish face
 Cephalometric studies show small sizes of the anterior and posterior
cranial bases and smaller mandibular dimensions, small posterior facial
height, and small posterior mandibular height.

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 Gigantism :
 The anterior facial heights appeared as the largest cephalometric
dimensions, followed by posterior facial height.
 Mandibular growth is gradual and often noticed by the dentist when
crossbite was developed.
 The calvarium, hands and feet grow by bone apposition.
 Mandibular growth in acromegaly results from both appositional
growth and hypertrophic changes in the condylar cartilage
 Effects on osteoblasts :
 GH stimulates the proliferation in a number of osteoblastic cell lines. It
stimulates the proliferation, differentiation and the production of type I
procollagen, osteocalcin and alkaline phosphatase in osteoblastic cells.
 The osteoblasts respond to GH by expressing bone morphogenetic
proteins (BMP) 2 and 4, which triggers a signalling pathway that
promotes osteoprogenitor cell differentiation and the upregulation of
osteoblast activity, and periodontal ligament (PDL) cells.

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 Effects on osteoclasts :
 GH stimulates osteoclastic bone resorption through both direct and
indirect (IGF-I and IL-6) actions on osteoclast differentiation
 Effects on mandibular condyle :
 GHR and IGF-I receptors are present in the chondroprogenitor and
chondroblast layers of the mandibular condyle
 Under GH excess, local IGF-I synthesis is stimulated; the mitotic activity
and the mature cells of the mandibular cartilage are increased, leading
to more endochondral ossification.
 Conversely, a lack of GH decreases mitotic activity through less IGF-I
synthesis, leading to less endochondral ossification.

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 Effects on maxilla :
 The maxilla is significantly reduced, and there may be a comparable
degree of reduction in the mandible.
 The maxilla is often retrognathic but is affected less than the mandible.
 Concerning cranial base size, many studies have reported that the
posterior cranial base length is smaller than the anterior cranial base
(N-S) length.

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 Hormones secreted by thyroid gland :
 Thyroxine (T4) ( 93 %)
 Tri-iodothyronine (T3) (7%)
 Eventually all of T4 is converted to T3
 Functions of both the hormones are same, but they differ in rapidity and
intensity of action
 T3 is almost 4 times more potent than T4, but stays for very less duration
and quantity in the blood as compared to T4
 Thyroglobulin :
 Large glycoprotein molecule secreted in the thyroid follicles
 It combines with iodine to form thyroid hormones

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 Formation of thyroid hormones :
 Formatin and secretion of thyroglobulin
 Oxidation of iodide ion
 Organification of thyroglobulin
 Storage of thyroglobulin

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 Release of thyroid hormones :
 Most of the thyroglobulin is not released, instead T3 and T4 are cleaved
and the free form of hormone are released in the circulation
 Daily secretion :
 About 35 mcg of T3 per day is delivered and used by the tissues
 Transport of hormones :
 Bound to plasma proteins
 Thyroxine binding globulin, thyroxine binding albumin and albumin
 Thyroxine and Triiodothyronine are released slowly to tissue cells
 On entering the cell, they again bind to intra-cellular proteins
 They have slow onset and long duration of action

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 Metabolism of thyroid :

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 PHYSIOLOGICAL FUNCTIONS :
 Increases the transcription of large number of genes
 In all cells of the body, great numbers of protein enzymes, structural
proteins, transport proteins, and other substances are synthesized
 They activate nuclear receptors
 Increases the cellular metabolic activity
 The rate of utilization of foods for energy is greatly accelerated.
 Although the rate of protein synthesis is increased, at the same time
the rate of protein catabolism is also increased.
 The growth rate of young people is greatly accelerated.
 The mental processes are excited.
 Increases the number and activity of mitochondria

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 EFFECT OF THYROID ON GROWTH :
 Has general and specific effects on growth
 Promotes growth and development of the brain during fetal life and for
the first few years of postnatal life.
 The effect of thyroid hormone on growth is manifest mainly in growing
children.
 In children with hypothyroidism, the rate of growth is greatly retarded.
 In children with hyperthyroidism, excessive skeletal growth often
occurs, causing the child to become considerably taller at an earlier
age.
 However, the bones also mature more rapidly and the epiphyses close
at an early age, so the duration of growth and the eventual height of
the adult actually may be shortened.

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 Effects of thyroid on specific body functions :
 Stimulation of carbohydrate and fat metabolism
 On plasma and liver fats, increased hormone levels decrease
cholesterol and phospholipid concentrations
 Increased requirement of vitamins due to high enzyme quantities
 Increased basal metabolic rate
 Increased cardiac activity
 Increased respiration
 Increased gastro-intestinal motility
 On muscles, excess hormones – weakened muscles
 Lack of hormone – sluggish muscles

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 Effect of Thyroid Hormone on Sexual Function:
 For normal sexual function, thyroid secretion needs to be
approximately normal.
 In men, lack of thyroid hormone - likely to cause loss of libido
 Excess of the hormone - sometimes causes impotence.
 In women, lack of thyroid hormone often causes menorrhagia and
polymenorrhea
 A lack of thyroid hormone may cause irregular periods and occasionally
even amenorrhea (absence of menstrual bleeding).
 Hypothyroidism is likely to result in a greatly decreased libido.
 With hyperthyroidism, oligomenorrhea (greatly reduced bleeding) is
common, and occasionally amenorrhea occurs.

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 HORMONE REGULATION :

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 TSH INCREASES THYROID SECRETION :
 Increased proteolysis of thyroglobulin
 Increased activity of iodide pump
 Increased iodination of tyrosine
 Increased size and secretory activity of thyroid cells
 Increased no of thyroid cells
 Cyclic adenosine monophosphate mediates the stimulatory effects
of TSH

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 Anterior pituitary secretion of TSH is regulated by thyrotropin-
releasing hormone from the hypothalamus
 1ST : To bind with TRH receptors in the pituitary cell membrane.
 2nd : This activates the phospholipase second messenger system
inside the pituitary cells to produce large amounts of
phospholipase C, followed by a cascade of other second
messengers, including calcium ions and diacyl glycerol, which
eventually leads to TSH release.
 Substances which suppress thyroid secretion :
 Thiocyanate
 Propyl-thiouracil
 High concentrations of inorganic iodide

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 Abnormalities of thyroid hormone secretion :
 Hyper-thyroidism
 Thyroid adenoma
 Hypo-thyroidism
 Myxedema
 Cretinism

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 THYROID HORMONE AND ORTHODONTICS :
 The cranial vault shows growth retardation in hypothyroidism, and
reduced facial height in children with prolonged untreated
hypothyroidism.
 Thyroxin administration seems to lead to increased bone
remodeling, increased bone resorptive activity and reduced bone
density.
 Thyroid hormones increased osteoclastic bone resorption
 Effects on bone tissue may be related to the augmentation of
interleukin-1 (IL- 1B) production that thyroid hormones induce at
low concentrations

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 A case report by Kim S et al, of 11 year old girl showed sudden
increase in orthodontic tooth movement of impacted canine at
certain periods which coincided with hyperthyroid periods. This
indicated possible relationship between the serum level of thyroid
hormone and the rate of orthodontic tooth movement

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 PARATHYROID GLAND :

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 Chemistry of parathyroid hormone :
 Pre-prohormone of 110 amino acid polypeptide chain synthesized on
ribosomes
 Prohormone of 90 amino acid chain
 Hormone of 84 amino acid chain
CLEAVED BY ENDOPLASMIC RETICULUM
GOLGI APPARATUS

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 Excess activity of the parathyroid gland causes rapid absorption of
calcium salts from the bones, with resultant hypercalcemia in the
extracellular fluid.
 Hypofunction of the parathyroid glands causes hypocalcemia, often
with resultant tetany.

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 PARATHYROID HORMONE EFFECTS ON CALCIUM AND PHOSPHATE
CONCENTRATIONS IN EXTRA-CELLULAR FLUID :
Rise in calcium concentration
occurs by 2 effects :
1. Effect of PTH to increase
calcium and phosphate
absorption from bone
2. Rapid effect of PTH to
decrease excretion of calcium
by kidneys
Decline in phosphate
concentration :
1. Effect of PTH to increase
renal phosphate excretion.

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 EFFECT OF PTH IN CALCIUM AND PHOSPHATE MOBILIZATION FROM BONE
 2 effects are seen by the action of PTH hormone
 1. Rapid phase of calcium and phosphate mobilization from bone—
osteolysis
 2. Slow phase of bone resorption and calcium phosphate release—
activation of the osteoclasts
 1. Rapid phase of calcium and phosphate mobilization from bone—
osteolysis
 PTH causes removal of bone salts from two areas in the bone:
 (1) from the bone matrix in the vicinity of the osteocytes lying within
the bone
 (2) in the vicinity of the osteoblasts along the bone surface.

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 The extensive system of the osteocytic membrane system is
believed to provide a membrane that separates the bone itself
from the extracellular fluid.
 Between the osteocytic membrane and the bone is a small amount
of bone fluid.
 The osteocytic membrane pumps calcium ions from the bone fluid
into the extracellular fluid, creating a calcium ion concentration in
the bone fluid only one third that in the extracellular fluid.
 When the osteocytic pump becomes excessively activated, the
bone fluid calcium concentration falls even lower, and calcium
phosphate salts are then released from the bone.

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 ROLE OF PTH IN OSTEOLYSIS :
 The cell membranes of both the osteoblasts and the osteocytes
have receptor proteins for binding PTH. PTH can activate the
calcium pump strongly, thereby causing rapid removal of calcium
phosphate salts from the amorphous bone crystals that lie near the
cells.
 PTH is believed to stimulate this pump by increasing the calcium
permeability of the bone fluid side of the osteocytic membrane,
thus allowing calcium ions to diffuse into the membrane cells from
the bone fluid
 Then the calcium pump on the other side of the cell membrane
transfers the calcium ions the rest of the way into the extracellular
fluid.

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 2. Slow Phase of Bone Resorption and Calcium Phosphate
Release—Activation of the Osteoclasts
 Since osteoclasts themselves do not have receptors for PTH, they get
activated by the secondary signals sent by osteoblasts and osteocytes.
 A major secondary signal is RANKL, which activates receptors on
preosteoclast cells and transforms them into mature osteoclasts that
set about their usual task of gobbling up the bone over a period of
weeks or months.
 Activation of the osteoclastic system occurs in two stages:
 (1) immediate activation of the osteoclasts that are already formed
 (2) formation of new osteoclasts

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 Parathyroid Hormone Decreases Calcium Excretion and Increases
Phosphate Excretion by the Kidneys
 Administration of PTH causes rapid loss of phosphate in the urine
as a result of the effect of the hormone to diminish proximal
tubular reabsorption of phosphate ions
 The increased calcium reabsorption occurs mainly in the late distal
tubules, the collecting tubules, the early collecting ducts, and the
ascending loop of Henle
 Parathyroid Hormone Increases Intestinal Absorption of Calcium
and Phosphate

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 Even the slightest decrease in calcium ion concentration in the
extracellular fluid causes the parathyroid glands to increase their
rate of secretion within minutes; if the decreased calcium
concentration persists, the glands will hypertrophy, sometimes
fivefold or more.
 Conditions that increase the calcium ion concentration above
normal cause decreased activity and reduced size of the
parathyroid glands.
 Such conditions include
 Excess quantities of calcium in the diet,
 Increased vitamin D in the diet, and
 Bone resorption caused by factors other than PTH (e.g., disuse of the
bones).

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 Changes in extracellular fluid calcium ion concentration are detected by a
calcium-sensing receptor in parathyroid cell membranes.
 The calcium-sensing receptor is a G protein–coupled receptor that, when
stimulated by calcium ions, activates phospholipase C and increases
intracellular inositol 1,4,5-triphosphate and diacylglycerol formation.
 This activity stimulates release of calcium from intracellular stores, which,
in turn, decreases PTH secretion.
 Conversely, decreased extracellular fluid calcium ion concentration
inhibits these pathways and stimulates PTH secretion.
 This process contrasts with that in many endocrine tissues in which
hormone secretion is stimulated when these pathways are activated.

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 Summary of PTH effects :

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 PARATHYROID HORMONE AND ORTHODONTICS :
 It could stimulate both osteoclast-mediated bone resorption and
osteoblast-mediated bone formation, therefore accelerating the bone
turnover rate.
 Systemic continuous infusion or local chronic application of parathyroid
hormone could accelerate tooth movement through enhancement of
alveolar bone resorption.
 Long-term intermittent injection of parathyroid hormone facilitated
periodontal repair of bone or root resorption after orthodontic tooth
movement through activation of osteoblastic cell
 Under intermittent parathyroid hormone administration, both osteoblast
and osteoclast activities are stimulated.

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 The anabolic effect of intermittent parathyroid hormone in the clinical
treatment of osteoporosis involves not only osteoblastic bone formation,
but also osteoclastic bone resorption.
 The ultimate increase of bone density is achieved through the “anabolic
window”
 Some researchers suppose that active osteoclastic resorption is necessary
for the effect of the parathyroid hormone on bone formation in a
remodeling system.
 Intermittent parathyroid hormone administration, results in an increase
in osteoclastic resorptive activity.
 In turn, the resorptive activity increases the release of osteogenic growth
factors from bone matrix and osteoclasts, and it stimulates bone
remodelling.

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 Calcitonin is a peptide hormone
secreted by the thyroid gland.
 It tends to decrease plasma
calcium concentration
 In general, it has effects
opposite to those of
parathyroid hormone.
 Synthesis and secretion of
calcitonin occur in the
parafollicular cells, or C cells.
 These cells constitute only
about 0.1 percent of the
human thyroid gland

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 Increased Plasma Calcium Concentration Stimulates
Calcitonin Secretion
• The primary stimulus for calcitonin
secretion is increased extracellular
fluid calcium ion concentration.
• An increase in plasma calcium
concentration of about 10 percent
causes an immediate twofold or
more increase in the rate of secretion
of calcitonin
• It provides a second hormonal
feedback mechanism for controlling
the plasma calcium ion concentration

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 Calcitonin Decreases Plasma Calcium Concentration
 It decreases the blood calcium concentration in 2 ways :
 The immediate effect is to decrease the resorptive activities of the
osteoclasts and possibly the osteolytic effect of the osteocytic membrane
throughout the bone, thus shifting the balance in favour of deposition of
calcium in the exchangeable bone calcium salts
 The second and more prolonged effect is to decrease the formation of
new osteoclasts. Also, because osteoclastic resorption of bone leads
secondarily to osteoblastic activity, decreased numbers of osteoclasts are
followed by decreased numbers of osteoblasts.
 Therefore, over a long period, the net result is reduced osteoclastic and
osteoblastic activity and, consequently, little prolonged effect on plasma
calcium ion concentration.

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 Calcitonin Has a Weak Effect on Plasma Calcium
Concentration in Adult Humans.
 Any initial reduction of the calcium ion concentration caused by calcitonin
leads within hours to a powerful stimulation of PTH secretion, which
almost overrides the calcitonin effect.
 When the thyroid gland is removed and calcitonin is no longer secreted,
the long-term blood calcium ion concentration is not measurably altered,
which again demonstrates the overriding effect of the PTH system of
control.
 In the adult human, the daily rates of absorption and deposition of
calcium are small, and even after the rate of absorption is slowed by
calcitonin, this still has only a small effect on plasma calcium ion
concentration

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 The effect of calcitonin in children is much greater because bone
remodeling occurs rapidly in children, with absorption and deposition of
calcium as great as 5 grams or more per day—equal to 5 to 10 times the
total calcium in all the extracellular fluid.
 Also, in certain bone diseases, such as Paget’s disease, in which
osteoclastic activity is greatly accelerated, calcitonin has a much more
potent effect of reducing the calcium absorption.

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 CALCITONIN AND ORTHODONTICS :
 In bones, calcitonin inactivates osteoclasts and thus inhibits bone
resorption by direct action on osteoclasts decreasing their ruffled surface
which forms contact with resorptive pit.
 It also stimulates the bone forming activity of osteoblasts.
 Because of its physiological role, it is considered to inhibit tooth
movement.
 Consequently, a delay in orthodontic treatment can be expected.

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 Normal value of calcium: 9.4 mg / dl of blood
 Calcium plays a key role in contraction of skeletal, cardiac, and smooth
muscles, blood clotting, and transmission of nerve impulses.
 Calcium concentration :
0.1% - extra cellular fluid
1% - cells and organelles
Rest – bones
 Phosphate concentration :
85% - bones
14% - cells
1% - extra cellular fluid

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 Inorganic phosphate in the plasma is mainly in 2 forms :
 1. HPO4
2-
 2. H2PO4
-
 The average total quantity of inorganic phosphorus represented by both
phosphate ions is about 4 mg/dl of blood.
NON BONE PHYSIOLOGICAL EFFECTS OF ALTERED CALCIUM AND
PHOSPHATE METABOLISM :
 Slight increases or decreases of calcium ion in the extracellular fluid can
cause extreme immediate physiological effects.
 Changing the level of phosphate in the extracellular fluid from far below
normal to two to three times normal does not cause major immediate
effects on the body.

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 Hypocalcaemia causes nervous system excitement and tetany :
 It causes increased neuronal membrane permeability to sodium ions,
allowing easy initiation of action potentials.
 At plasma calcium ion concentrations about 50 percent below normal,
the peripheral nerve fibers become so excitable that they begin to
discharge spontaneously.
 It initiates chains of nerve impulses that pass to the peripheral skeletal
muscles to elicit tetanic muscle contraction.
 Consequently, hypocalcaemia causes tetany. It also occasionally causes
seizures because of its action of increasing excitability in the brain.

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 Hypercalcemia depresses nervous system and muscle activity :
 When the level of calcium in the body fluids rises above normal, the
nervous system becomes depressed and reflex activities of the central
nervous system are sluggish.
 Increased calcium ion concentration causes lack of appetite and
constipation, probably because of depressed contractility of the muscle
walls of the gastrointestinal tract.
 These depressive effects begin to appear when the blood level of
calcium rises above about 12 mg/dl, and they can become marked as
the calcium level rises above 15 mg/dl.

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 Intestinal absorption of phosphate occurs easily.
 Almost all the dietary phosphate is absorbed into the blood from the gut
and later excreted in the urine, except for the portion of phosphate that is
excreted in the faeces in combination with non absorbed calcium.

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 Renal Excretion of Calcium and Phosphate:
 Approximately 100 mg/day of the ingested calcium is excreted in the
urine.
 Plasma calcium bound to plasma protein is not filtered by the glomerular
capillaries.
 The remainder is combined with anions such as phosphate (9 %) or
ionized (50 %) are filtered through the glomeruli into the renal tubules.
 Normally, the renal tubules reabsorb 99 % of the filtered calcium, and
about 100 mg/day are excreted in the urine.
 When calcium concentration is low, the reabsorption is great, and thus
almost no calcium is lost in the urine.

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 The most important factor controlling the reabsorption of calcium and
controlling the rate of calcium excretion, is parathyroid hormone.
 Renal phosphate excretion is controlled by an overflow mechanism
 When phosphate concentration in the plasma is below the critical value
of about 1 mmol/L, all the phosphate in the glomerular filtrate is
reabsorbed and no phosphate is lost in the urine.
 Above this critical concentration, the rate of phosphate loss is directly
proportional to the additional increase.
 Thus, the kidneys regulate the phosphate concentration in the
extracellular fluid by altering the rate of phosphate excretion in
accordance with the plasma phosphate concentration and the rate of
phosphate filtration by the kidneys.

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 The crystalline salts deposited in the organic matrix of bone are
composed principally of calcium and phosphate.
Hydroxyapatite does not precipitate in extracellular fluid despite super
saturation of calcium and phosphate ions.
 Inhibitors are present in almost all tissues of the body and plasma, to
prevent precipitation. Eg. pyrophosphate.
 Hence, hydroxyapatite crystals fail to precipitate in normal tissues except
in bone despite the state of super saturation of the ions.

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 Mechanism of bone calcification :
 Within a few days after the osteoid is formed, calcium salts begin to
precipitate on the surfaces of the collagen fibers.
 The precipitates first appear at intervals along each collagen fiber, forming
minute nidi that rapidly multiply and grow over a period of days and weeks
into the finished product, hydroxyapatite crystals.
 The initial calcium salts to be deposited are not hydroxyapatite crystals but
amorphous compounds (non-crystalline).
 Then, by a process of substitution and addition of atoms, or reabsorption
and re-precipitation, these salts are converted into the hydroxyapatite
crystals over a period of weeks or months.

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 The regulation of this process appears to depend to a great extent on
pyrophosphate, which inhibits hydroxyapatite crystallization and
calcification of the bone.
 The levels of pyrophosphate are regulated by tissue-nonspecific alkaline
phosphatase (TNAP), which breaks down pyrophosphate and keeps its
levels in check so that bone calcification can occur as needed.
 TNAP is secreted by the osteoblasts into the osteoid to neutralize the
pyrophosphate, and once the pyrophosphate has been neutralized, the
natural affinity of the collagen fibers for calcium salts causes the
hydroxyapatite crystallization.
 The importance of TNAP in bone mineralization is with genetic deficiency
of TNAP, which causes pyrophosphate levels to rise too high, children are
born with soft bones that are not adequately calcified.

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 The osteoblast also secretes at least two other substances that regulate
bone calcification:
1) nucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which
produces pyrophosphate outside the cells, and
2) ankyloses protein (ANK), which contributes to the extracellular
pool of pyrophosphate by transporting it from the interior to the surface of
the cell.
 Deficiencies of NPP1 or ANK cause decreased extracellular pyrophosphate
and excessive calcification of bone or even calcification of other tissues
such as tendons and ligaments of the spine, which occurs in people with a
form of arthritis called ankylosing spondylitis.

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Precipitation of calcium in non osseous tissues under abnormal
conditions.
 Although calcium salts usually do not precipitate in normal tissues
besides bone, under abnormal conditions, they can precipitate.
 For instance, they precipitate in arterial walls in arteriosclerosis and cause
the arteries to become bonelike tubes.
 Similarly, calcium salts frequently deposit in degenerating tissues or in old
blood clots.
 In these instances, the inhibitor factors that normally prevent deposition
of calcium salts disappear from the tissues, thereby allowing
precipitation.

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CALCIUM EXCHANGE BETWEEN BONE AND EXTRACELLULAR
FLUID
 If large quantities of calcium ions are removed from the circulating body
fluids, the calcium ion concentration again returns to normal.
 These effects result largely because the bone contains a type of
exchangeable calcium that is always in equilibrium with calcium ions in
the extracellular fluids.
 It amounts to about 0.4 to 1 percent of the total bone calcium. This
calcium is deposited in the bones in a form of readily mobilizable salt
such as CaHPO4 and other amorphous calcium salts.
 Importance: it provides a rapid buffering mechanism to keep calcium ion
concentration in the extracellular fluids from rising to excessive levels or
falling to low levels under transient conditions of excess or decreased
availability of calcium.

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 Deposition of bone by the osteoblasts :

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 Resorption of bone—function of the osteoclasts.

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 The bone-resorbing osteoclast cells do not have PTH receptors. Instead,
the osteoblasts signal osteoclast precursors to form mature osteoblasts.
 Two osteoblast proteins responsible for this signalling are receptor
activator for nuclear factor κ-B ligand (RANKL) and macrophage colony-
stimulating factor.
 PTH binds to receptors on the adjacent osteoblasts, stimulating synthesis
of RANKL, also called osteoprotegerin ligand (OPGL). RANKL binds to its
receptors (RANK) on preosteoclast cells, causing them to differentiate
into mature multinucleated osteoclasts. The mature osteoclasts then
develop a ruffled border and release enzymes and acids that promote
bone resorption.
 Osteoblasts also produce osteoprotegerin (OPG), also called
osteoclastogenesis inhibitory factor, a cytokine that inhibits bone
resorption.

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 OPG opposes the bone resorptive activity of PTH.
 Vitamin D and PTH appear to stimulate production of mature osteoclasts
through the dual action of inhibiting OPG production and stimulating
RANKL formation.
 The hormone estrogen stimulates OPG production.
 The balance of OPG and RANKL produced by osteoblasts therefore plays a
major role in determining osteoclast activity and bone resorption.

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Bone deposition and resorption are normally in equilibrium :
 Except in growing bones, the rates of bone deposition and resorption are
normally equal, so the total mass of bone remains constant.
 Osteoclasts usually exist in small but concentrated masses, and once a mass
of osteoclasts begins to develop, it usually eats away at the bone for about 3
weeks, creating a tunnel that ranges in diameter from 0.2 to 1 mm and is
several mm long.
 At the end of this time, the osteoclasts disappear and the tunnel is invaded by
osteoblasts instead; then new bone begins to develop.
 Bone deposition continues for several months, with the new bone being laid
down in successive layers of concentric circles (lamellae) on the inner surfaces
of the cavity until the tunnel is filled.
 Deposition of new bone ceases when the bone begins to encroach on the
blood vessels supplying the area.

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Value of continual bone remodeling.
 The continual deposition and resorption of bone have several
physiologically important functions.
1st: Bone adjusts its strength in proportion to the degree of bone
stress.
2nd: Even the shape of the bone can be rearranged for proper
support of mechanical forces by deposition and resorption of bone in
accordance with stress patterns.
3rd: Because old bone becomes relatively brittle and weak, new
organic matrix is needed as the old organic matrix degenerates.
In this manner, the normal toughness of bone is maintained.
 The bones of children, in whom the rates of deposition and absorption
are rapid, show little brittleness in comparison with the bones of the
elderly, in whom the rates of deposition and resorption are slow.

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Control of the Rate of Bone Deposition by Bone “Stress”
 Bone is deposited in proportion to the compressional load that the bone
must carry.
 Continual physical stress stimulates osteoblastic deposition and
calcification of bone, along with determining the shape of the bone.
 For instance, if a long bone of the leg breaks in its centre and then heals
at an angle, the compression stress on the inside of the angle causes
increased deposition of bone.
 Increased resorption occurs on the outer side of the angle where the
bone is not compressed.
 After many years of increased deposition on the inner side of the
angulated bone and resorption on the outer side, the bone can become
almost straight, especially in children because of the rapid remodelling of
bone at younger ages.

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Cholecalciferol (vitamin D3) is formed in the skin :
 Vitamin D3 (also called cholecalciferol) is the most important of the
several compounds of Vit D family and is formed in the skin as a result of
irradiation of 7-dehydrocholesterol, a substance normally in the skin, by
ultraviolet rays from the sun.
 Consequently, appropriate exposure to the sun prevents vitamin D
deficiency.
 The additional vitamin D compounds that we ingest in food are identical
to the cholecalciferol formed in the skin, except for the substitution of
one or more atoms that do not affect their function.

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Cholecalciferol Is Converted to 25-Hydroxycholecalciferol in the Liver :
 The 1st step in the activation of cholecalciferol is to convert it to 25-
hydroxycholecalciferol, which occurs in the liver.
 First, the feedback mechanism precisely regulates the concentration of
25-hydroxycholecalciferol in the plasma.
 The intake of vitamin D3 can increase many times and yet the
concentration of 25-hydroxycholecalciferol remains nearly normal.
 Second, this controlled conversion of vitamin D3 to 25-
hydroxycholecalciferol conserves the vitamin D stored in the liver for
future use.
 Once vitamin D3 is converted, the 25-hydroxycholecalciferol persists in
the body for only a few weeks, whereas in the vitamin D form, it can be
stored in the liver for many months.

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Formation of 1,25-dihydroxycholecalciferol in the kidneys and its
control by parathyroid hormone
 Conversion in the proximal tubules of the kidneys of 25-
hydroxycholecalciferol to 1,25-dihydroxycholecalciferol.
 This latter substance is by far the most active form of vitamin D because
the previous products have less than 1/1000 of the vitamin D effect.
 Therefore, in the absence of the kidneys, vitamin D loses almost all its
effectiveness.
 The conversion of 25- hydroxycholecalciferol to 1,25-
dihydroxycholecalciferol requires PTH.
 In the absence of PTH, almost none of the 1,25-dihydroxycholecalciferol is
formed.
 Therefore, PTH exerts a potent influence in determining the functional
effects of vitamin D in the body.

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ACTIONS OF VITAMIN D :
 The active form of vitamin D, 1,25-dihydroxycholecalciferol, has several
effects on the intestines, kidneys, and bones that increase absorption of
calcium and phosphate into the extracellular fluid and contribute to
feedback regulation of these substances.
 Vitamin D receptors are present in most cells in the body and are located
mainly in the nuclei of target cells.
 The vitamin D receptor forms a complex with another intracellular
receptor, the retinoid-X receptor, and this complex binds to DNA and
activates transcription in most instances.
 Although the vitamin D receptor binds several forms of cholecalciferol, its
affinity for 1,25-dihydroxycholecalciferol is roughly 1000 times that for 25-
hydroxycholecalciferol.

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“Hormonal” effect of vitamin D to promote intestinal calcium
absorption :
 1,25-Dihydroxycholecalciferol functions as a type of “hormone” to
promote intestinal absorption of calcium.
 It promotes this absorption principally by increasing, over a period of
about 2 days, formation of calbindin, a calcium-binding protein, in the
intestinal epithelial cells.
 This protein functions in the brush border of these cells to transport
calcium into the cell cytoplasm.
 The rate of calcium absorption is directly proportional to the quantity of
this calcium-binding protein.

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 Furthermore, this protein remains in the cells for several weeks after the
1,25-dihydroxycholecalciferol has been removed from the body, thus
causing a prolonged effect on calcium absorption
 Other effects are formation of :
(1) a calcium-stimulated adenosine triphosphatase in the brush
border of the epithelial cells and
(2) an alkaline phosphatase in the epithelial cells

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Vitamin D promotes phosphate absorption by the intestines:
 Although phosphate is usually absorbed easily, phosphate flux through
the gastrointestinal epithelium is enhanced by vitamin D.
 It is believed that this enhancement results from a direct effect of 1,25-
dihydroxycholecalciferol, but it is possible that it results secondarily from
this hormone’s action on calcium absorption, with the calcium in turn
acting as a transport mediator for the phosphate.
Vitamin D decreases renal calcium and phosphate excretion :
 Vitamin D also increases calcium and phosphate reabsorption by the
epithelial cells of the renal tubules, thereby tending to decrease excretion
of these substances in the urine.
 However, this effect is weak and probably not of major importance in
regulating the extracellular fluid concentration of these substances.

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Effect of vitamin D on bone and its relation to parathyroid hormone
activity.
 Vitamin D plays important roles in bone resorption and bone deposition.
 The administration of extreme quantities of vitamin D causes resorption of
bone.
 In the absence of vitamin D, the effect of PTH in causing bone resorption
is greatly reduced or even prevented.
 The mechanism of this action is not fully understood but is believed to
result from the effect of 1,25-dihydroxycholecalciferol to increase calcium
transport through cellular membranes.
 Vitamin D in smaller quantities promotes bone calcification.
 One of the ways it promotes this calcification is to increase calcium and
phosphate absorption from the intestines.

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Consequences of vitamin D deficiency :
 The function of vitamin D is to maintain serum calcium and phosphate
concentrations, which are important for many physiological functions.
 1,25(OH)2D is essential for the body’s ability to elevate intestinal calcium
absorption to 40% and intestinal phosphorus absorption to 80%, which
are necessary for skeletal well-being in humans.
 Inadequate exposure to sunlight in childhood causes devastating bone
deformities known as rickets.
 Researchers have linked vitamin D deficiency to muscle pain and muscle
weakness.

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 A strong correlation between low levels of vitamin D and incidence of
diabetes mellitus has been established. The incidence of type 2 diabetes
mellitus was 52% higher among individuals with vitamin D levels above 25
ng/mL compared to those with levels below 14 ng/mL.
 Links between the level of vitamin D and the incidence of autoimmune
diseases.
 Multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, and
Crohn’s disease are more common in high latitudes and in areas with low
sun exposure.
 This relationship was further supported by a number of experiments
demonstrating the role of vitamin D in regulating chemokine production,
counteracting autoimmune inflammation, and encouraging the
differentiation of immune cells.

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VITAMIN D AND ORTHODONTICS :
 A decrease in the serum calcium level stimulates secretion of parathyroid
hormone, which in turn increases excretion of PO4
3-, reabsorption of Ca2+
from the kidneys, and hydroxylation of 25, hydroxycholecaliferol to 1, 25,
DHCC.
 The latter molecule has been shown to be a potent stimulator of bone
resorption by inducing differentiation of osteoclasts from their
precursors.
 It is also implicated in increasing the activity of existing osteoclasts.
 In addition to bone-resorbing activity, 1, 25 DHCC is known to stimulate
bone mineralization and osteoblastic cell differentiation in a dose-
dependent manner

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 Another study by Kawakami M et al in 2004 concluded that local
applications of 1,25(OH)2D3 could enhance the reestablishment of dental
supporting tissues, especially alveolar bone, after orthodontic treatment.
 Increasing its concentration around paradental cells while they are
subjected to orthodontic forces can evoke synergistic reactions by the
cells, leading to rapid tooth movement.
 These factors might originate inside the patient, either locally or
systemically, such as cytokines and hormones or from external sources,
such as drugs and electric currents.
 Intra ligamentary injections of vitamin D metabolite, 1,25-dihydroxy
cholecalciferol, increases the number of osteoclasts and amount of tooth
movement during canine retraction with light forces as studied by Collins,
1988.

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 Another human study by Al-Hasani NR demonstrated that dose of 25 pg
calcitriol, produces 51% faster canine movement as compared to controls
without any damaging effect on surrounding tissues.
 Some investigators have suggested that in addition to faster teeth
movement, localized administration of vitamin D enhances tooth position
stability.
 In orthodontics, vitamin D deficiency may lead to a slower rate of tooth
movement, as evidenced by several laboratory-based investigations.

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Insulin and energy abundance :
 Insulin secretion is associated with energy abundance.
 In the case of excess carbohydrates, it causes them to be stored as
glycogen, mainly in the liver and muscles.
 All the excess carbohydrates that cannot be stored as glycogen are
converted under the stimulus of insulin into fats and stored in adipose
tissue.
 In the case of proteins, insulin has a direct effect in promoting amino acid
uptake by cells and conversion of these amino acids into protein.
 In addition, it inhibits the breakdown of proteins that are already in the
cells.

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Chemistry and synthesis :
 Insulin is composed of 2 amino acid chains linked by disulphide linkages.
 When these chains are split up, the function of insulin is lost.
 Blood circulation – in unbound form
 T1/2 : 6 mins

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Insulin and target cell receptors :

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Insulin and carbohydrate metabolism :
 Insulin promotes muscle glucose uptake and metabolism.
 Muscle tissue depends mostly on fatty acids for energy uptake.
 Muscles use large amount of glucose under the conditions –
1. Moderate or heavy exercise.
2. During the few hours after a meal.
 Insulin promotes liver uptake and storage of glucose.
 Effect of insulin is to cause most of the glucose absorbed after a meal to
be rapidly stored in the liver in the form of glycogen.

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Insulin and fat metabolism :
 The effects of insulin on fat metabolism are, in the long run, equally
important.
 The long-term effect of insulin deficiency is it causes extreme
atherosclerosis, often leading to heart attacks, cerebral strokes, and other
vascular accidents.
 Insulin increases utilization of glucose by most of the body’s tissues,
which automatically decreases the utilization of fat.

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EFFECT OF INSULIN ON PROTEIN METABOLISM AND GROWTH :
 Insulin and growth hormone interact synergistically to promote growth.

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 Insulin secretion :

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INSULIN AND ORTHODONTICS :
 No orthodontic treatment should be performed in a patient with
uncontrolled diabetes.
 A good oral hygiene is especially important when fixed appliances are
used, as they may increase plaque retention, which could more easily
cause tooth decay and periodontal breakdown.
 Diabetes related microangiopathy can occasionally appear in the
periapical vascular supply, resulting in unexplained odontalgia, percussion
sensitivity, pulpitis, or even loss of vitality in sound teeth.
 Especially in orthodontic treatments involving force application for
moving teeth over a considerable distance, the practitioner should
regularly check the vitality of the teeth involved.

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 As no upper age limit for orthodontic treatments is any longer valid today,
the practitioner will see both type 1 and type 2 DM patients.
 Type 2 patients can be considered more stable than type 1 patients, as
hypoglycemic reactions are more frequent in these patients.
 If a patient is scheduled for a long treatment session, he or she should be
advised to eat a usual meal and take the medication as usual.
 At each appointment, the orthodontist should confirm the meal and
medication, to avoid a hypoglycemic reaction in the office.
 DM patients with good metabolic control, without local factors, such as
calculus, and with a good oral hygiene, have a similar gingival status as
the healthy ones, consequently they can be treated orthodontically.

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 The principal estrogen secreted by the ovaries is β-estradiol.
 The estrogenic potency of β-estradiol is 12 times that of estrone and 80
times that of estriol.
 The estrogens mainly promote proliferation and growth of specific cells in
the body that are responsible for the development of most secondary
sexual characteristics of the female.
 In the normal nonpregnant female, estrogens are secreted in significant
quantities only by the ovaries.

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 SYNTHESIS OF ESTROGEN :

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Functions of estrogen :
 A primary function of the estrogens is to cause cellular proliferation and
growth of the tissues of the sex organs and other tissues related to
reproduction.
Effect of estrogens on the uterus and external female sex organs :
 During childhood, estrogens are secreted only in minute quantities, but at
puberty, the quantity secreted in the female under the influence of the
pituitary gonadotropic hormones increases 20-fold or more. At this time,
the female sex organs change from those of a child to those of an adult.
Effect of estrogens on the skeleton :
 Estrogens inhibit osteoclastic activity in the bones and therefore
stimulate bone growth.
 It is due to stimulation of osteoprotegerin, which is also called
osteoclastogenesis inhibitory factor, a cytokine that inhibits bone
resorption.

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 At puberty, when the female enters her reproductive years, her growth in
height becomes rapid for several years.
 However, estrogens have another potent effect on skeletal growth: They
cause uniting of the epiphyses with the shafts of the long bones.
 This effect of estrogen in the female is much stronger than the similar
effect of testosterone in the male.
 As a result, growth of the female usually ceases several years earlier than
growth of the male.
Estrogens slightly increase protein deposition :
 Estrogens cause a slight increase in total body protein.
 This effect mainly results from the growth-promoting effect of estrogen on
the sexual organs, the bones, and a few other tissues of the body.

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Osteoporosis of the bones caused by estrogen deficiency in old age :
 After menopause, almost no estrogens are secreted by the ovaries.
 This deficiency leads to :
(1) increased osteoclastic activity in the bones,
(2) decreased bone matrix, and
(3) decreased deposition of bone calcium and phosphate.
 In some women this effect is extremely severe, and the resulting condition
is osteoporosis.
 Because osteoporosis can greatly weaken the bones and lead to bone
fracture, especially fracture of the vertebrae, many postmenopausal
women are treated prophylactically with estrogen replacement to prevent
the osteoporotic effects.

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ESTROGEN AND ORTHODONTICS :
 Estrogen directly stimulates the bone-forming activity of osteoblasts, so it
is reasonably to expect a slower rate of orthodontic tooth movement.
 Estrogen decreases the rate of bone resorption.
 Estrogen inhibits the production of various cytokines, mainly interleukin-1
(IL-1), tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6), which
are involved in bone resorption.
 Estrogens do not have any anabolic effects on bone tissue; they directly
stimulate the bone forming activity of osteoblasts.

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Effect on tooth movement :
 Tooth movement occurs as a consequence of periodontal tissue remodelling
when force is applied to teeth.
 The process of periodontal tissue remodelling involves the following:
1. Stretching of the periodontal ligament and deposition of the new alveolar
bone at the tension region.
2. Compression of the periodontal ligament and the resorption of the alveolar
bone at the pressure region.
 The rate of periodontal tissue remodelling is influenced by various factors
such as the estrogen level.
 Previous studies have shown the presence of estrogen receptors in the
periodontal tissue, indicating that this tissue is targeted by estrogen.

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 Estrogen influences the composition and degradation of collagen fibers in
the periodontal ligaments and the remodelling of the alveolar bones.
 While estrogen influences the deposition and cross-linking of collagen
fibers, it also enhances the alkaline phosphatase (ALP) activity and the
secretion of osteocalcin (OCN) and osteoprotegerin (OPG) in the
periodontal ligament cells (PDLCs).
 Estrogen inhibits tooth movement by increasing the bone mineral content
and bone mass and by reducing the bone resorption rate.
 Several studies have shown that estrogen deficiency and accelerated
tooth movement.

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 Celebi et al reported orthodontic tooth movement association with
ovarian activity. PGE2 and interleukin 1 are increased in ovariectomized
and anestrous cat groups resulting in greater tooth movement.
 Xu X et al also stated that tooth movement is faster when estrogen levels
are low. Therefore orthodontic treatment should be planned according to
menstrual cycle.
 Another study showed association of tooth movement with ovulation and
menstruation. Orthodontic tooth movement would be faster if
orthodontic force applied during menstruation as estrogen levels are low
at this time and tooth movement would decrease during ovulation.
 Hence, orthodontist may accelerate tooth movement by doing activation
of orthodontic appliances during menstruation.

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 Most of the studies on hormones have been done on rats, squirrels and
monkeys and not on human beings; hence, very little is still known on the
effects of hormones on the development of face and craniofacial skeletal
and on the rate of orthodontic tooth movement in humans.
 Hormones can be beneficial or detrimental to tooth movement that is
accelerating or decelerating the tooth movement and consequently
increase or decrease the duration and efficiency of the treatment.
 The role of endocrine disorders in orthodontics is still a great mystery for
an orthodontic practitioner and further research is required to
understand it better.

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