ENDOCRINE PHYSIOLOGY

HORMONE PHYSIOLOGY

PRINCIPLES

 Hormones are involved in regulation of homeostasis, but they take longer to have their
effect than neurons
 Hormones are mainly involved in: metabolism, growth, reproduction, differentiation,
fluid and electrolyte balance
 Hormone: substance secreted into interstitial fluid by ductless gland which is carried
by blood to the target tissues it affects
 Humoral communication: neural, endocrine, paracrine, autocrine, juxtacrine (used
mainly by the nervous system, growth initiated by contact between cells)

Endocrine Communication

Classic Glands

 Hypothalamus: Gonadotrophin-releasing Hormone (GnRH), CRH, TRH, somatostatin,

ADH
 Pituitary gland: growth hormone, prolactin, ACTH, MSH, TSH, FSH, LH, oxytocin, ADH
 Pancreas: insulin, glucagon
 Ovaries: Oestrogens, progesterone
 Epiphysis cerebri/pineal gland: melatonin
 Thyroid Gland: T3, T4, Calcitonin
 Parathyroid Glands (4): Parathyroid hormones
 Adrenal Cortex: cortisol, Aldosterone, androgens
 Adrenal Medulla: catecholamines

Less Traditional Sources

 Endothelium: endothelins, nitric oxide, prostanoids

 Immune System: cytokines
 Platelets and Mesenchyme: growth factors
 Placenta: all hormones
 Adipocytes: leptin (deficiency of this causes obesity)
 Cardiocytes: ANP
 Kidney: erythropoietin, RAS
 Gastrointestinal Tract: gastrin, cholecystokinin, secretin
 Gonads: inhibins, activins

Categories of Hormones

1
  Peptides: eg insulin
 Glycoproteins: eg FSH, TSH, hCG
 Amines: eg catecholamines, thyroid hormones
 Steroids: eg oestrogens, progesterone

Synthesis

 Peptides and receptors: synthesis regulated at level of transcription

 Amines and steroids: synthesis regulated indirectly by altering production of key
synthetic enzymes and substrate availability
 Peptides: majority are synthesized initially as large polypeptide chains then processed
intracellularly by proteases to give final molecule. Several can come from the same
precursor. Transcription can be directly affected by hormones binding to receptors in
regulatory regions of the gene coding for the molecule.
 Precursors are commonly inactive
 Steroids are synthesized from cholesterol

Storage

 Most tissues which synthesize hormones have a limited capability of storing them
 Nerves have a greater capacity to store hormones
 Most are difficult to store
 Steroid hormones are too polar to store in lipid
 Peptides are unsuitable to be stored by incorporation into proteins
 Polar hormones are more likely to be stored, lipids are more likely to be synthesized on
demand
 Precursor hormones can be stored as either protein or in neutral lipid, vitamin D
precursors

Release Mechanisms

 Are incompletely understood

 Is exocytosis for many hormones
 Peptides, glycoproteins, amines: exocytosed when activated by a signal (eg
neurotransmitter or peptide releasing factor)
 Exocytosis: influx of calcium ions, vesicles travel down microtubules using
kinesin/myosin then fuse to membrane
 Steroids: by diffusion controlled by kinetic influences on synthetic enzymes or carrier
proteins involved in their secretion (eg by StAR protein which has to be synthesized
by activation of transcription factor, phosphorylated then bound to mitochondria to
facilitate entry of precursors into them for synthesis of steroids)

2
  Most are released at a rate reflecting their production even for those stored as
granules
 Rate of release can be periodic or rhythmic
 Rhythmic release: ultradian (minutes to hours; eg appetite), circadian (daily; eg ACTH),
infradian (weekly to yearly; eg menstrual cycle)
 Pulsatile secretion: eg gonadotrophins in a “secrete-stop-secrete-stop”manner

Transport

 Can be transported in blood, lymph, ECF from site of release to site of cellular action
 Water insoluble hormones are bound to proteins
 Protein-bound hormones cannot enter cell: act as a reservoir from which free hormone
can be liberated and diffuse into the cell
 Regulated by: rate of degradation/uptake, receptor binding, availability of receptors,
affinity of hormone for plasma carriers
 Stability influenced circulating half-life of hormone
 Plasma carriers: serve as reservoir for inactive hormones (bound hormones are
prevented from degradation/uptake) so fluctuations in hormonal levels can be
smoothed out over time, restrict access of hormone to some sites
 Steroid hormones: mostly bound to large proteins, steroid binding proteins (SBPs)
synthesized in the liver. Only small amounts are dissolved in plasma
 Sex hormone binding globulin (SHBG): glycoprotein which binds to testosterone, 17β-
estradiol. SBP-hormone and free hormone are in equilibrium in plasma.
 Functions of SBPs: increase solubility of lipid based hormones in blood, reduce rate of
hormone loss through kidneys (prevent them from being filtered due to size), provide
a source from which hormone can be released from blood as equilibrium changes
 Regulating expression and secretion of binding proteins regulates availability of
hormones, important for regulating availability of thyroid hormones
 Transcortin: binds to progesterone, cortisol and other corticosteroids
 Anatomical relationship between sites of release and sites of action regulates
hormones: eg some are destroyed by passage through pulmonary circulation or the
liver

Degradation and Turnover

 Plasma level of hormone is dependent on: secretion rate, rate of metabolism, rate of
excretion
 Metabolic clearance is accomplished by many mechanisms
 Degradation can take place in target and non-target cells
 Only small fraction of intact hormones is secreted in urine or bile

3
Hormone Action

Peptides/catecholamines

 Have receptors in cell membrane: most are GPCRs

 Have fast action
 Use second messengers to change protein activity which ultimately alters protein
activity

Steroid/thyroid hormones

 Can have cytosolic or nuclear receptors

 Predominantly exert their effects via nuclear receptors
 Nuclear receptors: direct stimulation of transcription by binding of transcriptional co-
activator when hormonal ligand is bound, regulation of genes targeted by the hormone
 Have slower action that peptides
 Change gene expression

Membrane Receptors

 Can activate phospholipase C with production of DAG/IP3 (Ca2+ calmodulin binding): eg

Angiotensin II
 Can increase cAMP: eg PTH
 Can increase cGMP: eg ANP, NO
 Can increase tyrosine kinase activity: eg insulin
 Can increase serine-threonine kinase activity: use SMAD as second messenger
 NB: one hormone can use several types of receptor in various cells for different
functions

Magnitude of response

Depends on

 Concentration of hormone
 Number of receptor molecules
 Duration of exposure
 Intracellular conditions: second messengers, kinases
 Synergistic or antagonistic influences: can be other hormones

Hormone Quantification

Measurement of hormone concentration can be done using three methods:

 Bioassays

4
  Radioimmunoassay
 ELISA

Bioassay

 Hormone is quantified in terms of biologic response produced

 Rarely used for modern diagnostic purposes

Radioimmunoassay

HYPOTHALAMUS AND PITUITARY

 Are a consortium forms the most complex control centre of the body
Hypothalamus
 Lies below thalamus, is part of the diencephalon
 Epithalamus is above thalamus and hypothalamus
 Contains many nuclei: supraoptic nuclei, paraventricular nuclei
 Controls: satiety, hunger, responses to heat and cold, thirst, sexual function
 Anterior hypothalamus: controls the parasympathetic nervous system, response to he
at/heat-dissipating mechanisms
 Posterior hypothalamus: controls the sympathetic nervous system, response to cold/h
eat-conserving mechanisms
 Hypothalamus was once called the head ganglion of the autonomic system”
 Medial part of the hypothalamus: controls satiety, dysfunction results in obesity (pers
on will not feel full after eating)
 Lateral part of the hypothalamus: controls hunger, dysfunction results in wasting of th
e patient (person will not feel hungry)
 Thirst: hypothalamus has osmoreceptors in anterior part which sense the osmolality of
blood. High osmolality will make the hypothalamus stimulate pituitary to release ADH
 Angiotensin II: acts on the subfornical organ to stimulate neural areas associated wit
h thirst
Pituitary gland
 Is also called the hypophysis
 Is within a bone that looks like a horse saddle (sella turcica)
 Connected to hypothalamus by pituitary stalk

5
  Pituitary: anterior and posterior
 Posterior: connected to hypothalamus through nerves, produces oxytocin and ADH, dev
elopes from diencephalon. Has pituicytes (glial cells)
 Anterior: connected to hypothalamus by blood vessels (portal system), produces GH, F
SH, ACTH, TSH, LH prolactin-hypophysiotropic hormones, develops from buccal mucos
a membrane. Has chromophils (take up dye, have endocrine function: acidophils secrete
growth hormone and prolactin, basophils secrete the rest) and chromophobes (do not t
ake up dye)
 Both glands come from ectoderm
 Oxytocin and ADH are stored and secreted by posterior pituitary: does not synthesize
(cell bodies in hypothalamus, nerve ending is in posterior pituitary)
 Anterior pituitary: synthesizes, stores and secretes hormones, exposed to higher hor
mone concentrations-most are peptides except dopamine
 Pituitary can be influenced by sleep, pain, thought, close to autonomic nervous system
to allow integration. Receives hormones at a higher concentration than rest of the bod
y, essential for function of pituitary (pituitary needs high concentration, needs to be c
lose to hypothalamus)
 Hypothalamus releases hormones which inhibit or activate synthesis/secretion of horm
ones in the anterior pituitary
Hypothalamic functions
 Receives afferents from different parts of the brain
 Eyes: day or night, via retinohypothalamic fibers to the suprachiasmatic nucleus
 Reticular: wakefulness
 Neocortex: planning, defensive actions
 Thalamus: everything from brain
 Limbic: emotions

Hypophysiotropic Hormones
 Secreted by median eminence of hypothalamus which influence pituitary function
 Include: CRH, TRH GnRH, GHRH, dopamine, serotonin
 One factor can cause release of many hormones
 Somatostatin: inhibits GH secretion and TSH secretion
 TRH: stimulates secretion of TSH and prolactin
 GnRH: stimulates secretion of FSH and LH
6
  CRH: stimulates secretion of ACTH and beta lipotrophin

Clinical correlates of Hypothalamus

Kallman syndrome: hypogonadotrophic hypogonadism with partial or complete loss of smell/ol
faction. GnRH neurons embryologically develop in the nose and migrate along the olfactory ne
rves to the hypothalamus, so if the migration is stopped by malforming olfactory pathways th
en the patient will have Kallman syndrome

Posterior Pituitary
 Secretes vasopressin (ADH) and oxytocin
 Are nonapeptides: have 9 amino acids
 Are only different at 2 positions, are very similar in structure
 Synthesized in the hypothalamus
 Vasopressin: mainly synthesized by supraoptic nuclei
 Oxytocin: mainly synthesized by paraventricular nuclei
 Due to similarity in structure, ADH has 20% oxytocin activity, oxytocin has 0.5% activi
ty of ADH
 ADH can act as oxytocin more so than oxytocin can act as ADH
 ADH and oxytocin both have specific neurophysins associated with them in granules
 Neurophysin: 10 kDa protein, has versions I and II. They are part of the precursor mo
lecules
 Neurophysin I is associated with oxytocin
 Neurophysin II is associated with ADH
 Synthesis: by ribosomes, then leader sequence is removed in the ER, put into secretor
y granules called Herring bodies
 Vasopressin and oxytocin are also produced by gonads and adrenal cortex

Vasopressin/ADH
 Synthesis: in magnocellular neurons of the supraoptic and paraventricular nuclei (mainl
y the supraoptic nuclei)
 Is a stress hormone, also increases secretion of other stress hormones
 Causes vasoconstriction
 Prevents passage of water in urine, for reabsorption of water by kidneys
 Acts on V1 and V2 receptors
7
  V1: can be V1a or V1b which both use calcium as second messenger
 V2: uses cAMP as second messenger
Effects:
 Increases permeability of collecting ducts to water
 Causes excretion of concentrated urine: excretion of excess plasma solutes and minim
al water
 Causes vasoconstriction
 Increases glycogenolysis in liver
 Depresses cardiovascular centres
 Increases ACTH secretion from corticotrophs, increases secretion of cortisol
 Increases synthesis of factor VIII: in pharmacological doses. Used to treat mild haem
ophilia (giving vasopressin in pharmacological doses)
Increasing permeability of collecting ducts to water
 Is through V2 receptors
 Increases PKA which increases mobilisation of vesicles containing aquaporin 2 molecule
s
 Aquaporin 2 molecules in membrane on luminal side are increased, more water channels,
more water goes into cells of collecting ducts
 7 different types of aquaporins
Control of ADH secretion
Factors increasing secretion:
 Increased osmotic pressure in plasma
 Reduction in blood volume
 Pain, emotion, exercise, stress
 Nausea, vomiting
 Standing: blood pools in the legs, reducing blood volume
 Angiotensin II
 Adrenergic stimuli
 Nicotine, morphine, carbamazepine
Factors reducing secretion
 Reduced osmotic pressure
 Increase in ECF
 Alcohol: OH groups
 Parasympathetic innervation
8
Clinical Correlates
Excess ADH:
 syndrome of inappropriate ADH secretion SIADH-very common
 Due to diseases in cerebrum or in the lung (pulmonary TB, pneumonia, small cell lung ca
ncer caused by smoking)
 Results in hyponatremia
Insufficient ADH
 Leads to diabetes insipidus
 Resistance of ADH
 Large volumes of urine passed (3 litres or more)
 Can be neurogenic or Nephrogenic
 Neurogenic DI: insufficient ADH from pituitary or defects in hypothalamus which caus
e less secretion of ADH by pituitary
 Receptor resistance
Nephrogenic diabetes insipidus
 X linked
 Kidneys not responding to ADH
 Due to lithium, hypercalcemia or hyperkalemia which cause ADH resistance
 Can be treated using thiazide diuretic
 Desmopressin (ADH analog) given to tell between nephrogenic and neurogenic DI: in ne
urogenic DI then the kidneys will respond to desmopressin, but in Nephrogenic DI the
kidneys will not respond

Oxytocin
 Speeds up labour
 Promotes labour
 Receptors use calcium as second messenger : increases contractility of muscle
 Also found in the thymus
Actions:
 Acts primarily on the uterus and breasts
 Important for milk let down reflex in mammary gland, causes contraction of myoepithe
lial cells
 Ejaculation in males
 May be involved in luteolysis: degradation of corpus luteum
9
  May be responsible for propulsion of sperms in the female during or after intercourse
Control of secretion
Increased by:
 Tender thoughts
 Sexual stimulation
Decreased by:
 Alcohol
 Stress
 Breastfeeding under embarrassing conditions
 Anger

ANTERIOR PITUITARY
 Hormones divided into 3 three groups
ACTH related peptides:
 B endorphin, B lipotrophin, B MSH
Glycoproteins:
 FSH TSH and LH
 Have alpha and beta subunits
 Alpha: identical and have no biological activity
 Beta: give specificity, alone have little biological activity. Have to be bound to alpha su
bunits to exert their full biological effect

Somatommamotropins
 Prolactin and growth hormone

GROWTH HORMONE
 Doesn't mediate growth on its own
 Secreted by Somatotrophs of pars distalis
 Some of its effects are mediated by somatomedins
 Release is controlled by GHRH and GHIH (Somatostatin)
 Wide range of metabolic effects which may affect all types of cells
 Can increase production of milk: lactogenic activity
Secretion
 Reflects metabolic requirements: decreased glucose, increased amino acids
 Neural factors: stress, neural stress, sleep
Gene
 On long arm of chromosome 17
10
  Bound to a protein in plasma which is a large fragment of its receptor
 Concentration of fragment indicates how many receptors in tissues
Effects
Liver:
 Increases RNA and protein synthesis
 Increases gluconeogenesis and glycogenolysis
Adipose tissue:
 Decreases glucose uptake
 Increases lipolysis
 Reduces adipocity
Muscle
 Reduces glucose uptake
 Anti-insulin effect in muscle
Gastro-intestinal tract
 Increases calcium absorption
Kidneys
 Decreases sodium and potassium excretion
Somatomedins
 Secreted by liver
 Insulin-like growth factor 1: somatimedin C, effect on chondrocytes, affected by gro
wth hormone
 IGF 2
 IGF receptor is similar to that of insulin
 IGFs important in embryonic development
Effects
 Increases protein synthesis
 Increase RNA synthesis
 Increase DNA synthesis
 Increase cell size and number
 Leads to increased organ size and function
Effects on chondrocytes
 Increases collagen
 Increases chondroitin sulfate
 Increase in linear growth
 Increase amino acid uptake
Other effects
 Stimulate myelin synthesis and neuronal survival
Factors controlling GH release
 Decrease in glucose and free fatty acids
 Increase in amino acids
 Fasting and prolonged caloric deprivation
 Deep sleep
 Exercise
 Stress: pain
11
 Androgens and oestrogens
Dopamine and serotonin
Enkephalins and endorphins
Ghrelin
Inhibition of Growth Hormone secretion
 Glucose increase
 Cortisol
 Obesity
 Pregnancy
 Somatostatin
 GH itself: IGF 1
Affected by
 Thyroid hormones
 Insulin
 Glucocorticoids
 Nutrition
 Genetic factors
Role of nutrition
 Food supply is the most extrinsic factor affecting growth
 Fasting and protein deprivation decrease IGF secretion
 Age at which deficiency occurs is important
Growth Period
 Two periods of rapid growth in life
 Infancy: thyroid hormones are critical, permissive to effects of GH, potentiate IGF, n
ecessary for normal GH secretion
 Late puberty before growth stops: due to GH and sex hormones, ehiphyses close
 Sex hormones increase spikes of IGF release, estrogens cause closure of epiphyseal gr
owth plates (women stop growing earlier than men)
 Insulin deficiency causes decrease in IGF
 Glucocorticoids can stop growth in children
Catch-up Growth
 People who grow slowly then catch up by growing faster than normal later on
 Occurs in periods of severe stress, children don't grow

Short Stature
 Anyone less than 1.46m tall
Can be due to:
 GHRH deficiency
 GH deficiency
 Deficient secretion of IGF 1
 Other causes: nutrition, thyroid, cartilage, collagen, precocious puberty, cretinism, gon
adal dysgenesis (Turner Syndrome), achrondoplasia
Laron Dwarfs
 Due to GH insensitivity: GH is present but not stimulating IGF, receptor for GH not re
12
 sponsible
African Pygmies
 Normal GH and a modest decrease in plasma level of GHBP
 Growth is normal until puberty
Achrondoplasia
 Normal trunk
 Short limbs
 Mutation in gene that codes for fibroblast growth receptor 3
 Is inherited

Prolactin
 Secreted by acidophils
 Has receptors which resemble those of GH
 Under predominant inhibition by the hypothalamus using dopamine
Secretion increased by
 Sleep
 Nursing
 Breast stimulation in non-lactating females
 Stress
 Hypoglycaemia
 Exercise
 Pregnancy
 Hypothyroidism
 Oestrogen
 Sexual intercourse
 Histamine antagonist eg cimetidine (used to treat ulcers)
 Dopamine antagonists
Secretion decreased by
 Dopamine: main inhibitor of prolactin
 Bromocriptine
 Prolactin: hormone inhibits its own secretion
Effects
 Breast development
 Causes milk secretion from breast after oestrogen and progesterone priming
 Inhibits LH and FSH
Prolactin deficiency
 Causes woman to be unable to lactate
Hypersecretion causes hyperprolactinamia

Hyperprolactinemia
 Caused by chromophobic adenoma arising from damage to pituitary stalk (no control fr
om hypothalamus which inhibits secretion)
 Tumours secreting prolactin
Characterised by
13
  Loss of menses
 Decreased libido
 Anovulation
 Infertility (less often)
 Galactorrhea- lactation unassociated with pregnancy
 Gynecomastia (less common)- breast development in men, common in teenage boys, obe
se boys
 Hirsutism: occurs in women, have hair in abnormal places

Excessive production of Growth hormone

 Leads to giganticism: excessive growth before epiphyses close
 Leads to acromagaly: growth after epiphyses close
 Microadenoma: less than 10mm long
 Macroadenoma: more than 10mm long
Causes of acromegaly
 Pituitary excessive secretion
 Pancreatic islet tumour, lymphoma: produce growth hormone
 GHRH excess

Acromegaly
 Enlarged hands and feet
 Hands are spread
 Protruding chin: prognathism
 Coarse facial features: bulbous, prominent bony ridges, hirsutism (women), gynaecoma
stia in men, lactation in women (GH has intrinsic effects on prolactin secretion)
 Osteoarthritic vertebral changes
 Acral and facial changes: acral is to do with hands and feet
 Hyperhydrosis: excessive sweating
 Oily skin
 Headaches
 Carpal tunnel syndrome: growth of bones in hand presses on nerves (particularly the m
edian nerve in Carpal Tunnel Syndrome)
 Glucose intolerance: when glucose tolerance test is done, glucose is given, but GH secr
etion does not go down in response to it
 Hypertension
 Sexual dysfunction
 Cardiac failure: heart becomes big
 Visual field changes: rare
 Proximal myopathy: muscle close to trunk are weak, not able to stand from sitting posi
tion, not able to go up stairs, not able comb hair
Management
 Surgery for pituitary adenoma
 Somatostatin agonists
 Growth hormone analog which inhibits GH secretion
14
β MSH and β Lipotrophin
 β lipotrophin for mobilisation of fat
 β MSH: increases stimulation of melanocytes: same number of melanocytes in all races
, melanin production differs. Is melanocyte-stimulating hormone
 ACTH causes skin pigmentation

Other anterior pituitary hormones

 Regulate function of peripheral glands

Pituitary hyperfunction
 Causes acromegaly
 Cushing's disease
 Hyperprolactenemia
Pituitary insufficiency
 Anterior pituitary tumours
 Infarcts of pituitary: blood supply to it is compromised, Sheehan syndrome (decreased
perfusion of pituitary after giving birth→hypopituitarism)
Characterised by
 Growth inhibition
 Hypothyroidism
 Hypogonadism
 Inability to cope with stress
 Pallor
 Wasting is not a feature of this condition

THYROID GLAND
 Has two lobes, found in the neck in front of the trachea
 Two lobes connected by an isthmus, can have a pyramidal lobe on the isthmus
 Seen in women who come from mountainous areas
 Moves when you swallow
 Increases in size during pregnancy
 Has follicles: layer of squamous cells with colloid in the middle. Outside the layer (in th
e interstitium) are parafollicular C cells which produce calcitonin. Follicle produces T3
and T4 (thyroxin)
 Calcitonin is thought to be involved in calcium metabolism, causes bone to absorb calciu
m from blood
 Cells become more cuboidal and decrease colloid space when active
 Follicles take up iodine (active transport by sodium/iodide symport using sodium gradie
nt)
 150micrograms of iodide required daily
 The higher the altitude, the lower iodide concentration
 NaI: NaCl in iodised table salt is 1:10 000
 Iodide deficiency is more common in women
15
Hormones secreted
 T3 and T4
 Calcitonin
 Under control of pituitary
 T3 and T4 exert long loop feedback on TRH secretion by hypothalamus
 TSH increases: iodide trapping, size of gland, synthesises of T3 and T4. Uses cAMP
 (growth hormone and prolactin are the only pituitary hormones which use tyrosine kina
se, the rest use cAMP)
Synthesis of hormones
 Thyroglobulin found in colloid containing several tyrosine residues, is taken up by endo
cytosis, combines with lysosomes then T4 and T3
 Iodide is oxidised to iodine using thyroid peroxidase
 Iodine is inserted on tyrosine residues to form diiodotyrosine (DIT) or monoiodotyrosi
ne (MIT) by thyroid peroxidase
 When two diiodotyrosine molecules combine, T4 is formed
 When diiodotyrosine and monoiodotyrosine combine, reverse T3 formed which has no p
hysiologic function
 T3 and T4 are transported in blood bound to proteins
 Thyroid-binding globulin (TBG), albumin, transthyretin (prealbumin) bind to thyroid h
ormones to transport them through blood
 99.98% of thyroid hormones in blood are bound to protein
Secretion increased by
 Need for metabolic activity
 Low temperature
 Stress
Secretion decreased by
 Dopamine and somatostatin: act on pituitary to reduce TSH secretion
 Glucocorticoids: inhibit TSH secretion
Role of thyroid hormones
 Increase basal metabolic rate:
 Increase glycolysis
 Increase blood flow
 Increase in activity of enzymes of ETC
 Increase uncoupling in brown fat, producing more heat increasing basal temperature
 increase synthesis of beta adrenergic receptors: increase contractility of heart, incre
ase heart rate
 Increase in conversion of carotene to vitamin A
 Increase synthesis of LDL receptors (more cholesterol taken up, lowering cholesterol
levels in blood)
 Increase synthesis of alpha myosin heavy chain in the heart, increasing contractility of
muscle in heart
 Increase myelination of neurons, involved in maturation of the nervous system
 Important for release of Growth hormone
 Increase in gastric motility
16
  Increases glucose absorption in GIT
 Increase oxygen consumption of almost all metabolically active tissues
 Increase activity of Na+/K+ ATPase
Mechanism of Action
 Bind to intracellular receptors
 Receptor-hormone complex binds to zinc fingers
 Increases/decreases expression of genes coding for proteins which regulate cell funct
ion
Receptors
 Hormones have a similar structure to catecholamines
 Can bind to catecholamine receptors
 Are mostly intracellular
 Alpha and beta receptors
 Beta usually found in the brain, abnormal isoforms cause ADHD (abnormal maturation o
f CNS)
 Alpha found peripherally, abnormal isoforms cause thyroid hormone resistance

Thyroid hormone excess

Hyperthyroidism
 Primary: due to thyroid gland, T3 inhibits T4
 Secondary: due to pituitary
 Tertiary: due to hypothalamus
 Subclinical: low TSH but normal T4
Causes
 Grave's disease
 Multi-nodular goitre
 Toxic multi-nodular goitre
Iodine effect
 Usually in women: factitious due to taking thyroid hormones to lose weight
Caused by:
 Tumour of ovaries which produces hCG (similar stucture to TSH, stimulates thyroid ho
rmones release)
Characterised by
 Muscle weakness of skeletal muscle (thyrotoxic myopathy): increased protein cataboli
sm
 People who are very thin
 Increased heart rate
 Weight loss despite adequate caloric intake
 Overly anxious
 Problems sleeping
 Heat intolerance
 Cardiomyopathy/high output cardiac failure
 Cardiac failure
 Tremors
17
  Fast relaxation phase with knee-jerk reflex: fast knee-jerk reflex
Grave's specific signs:
 More common in women aged 20-40
 Exopthalmus
 Acropachy
 Thyroid stimulating immunoglobulins bind to receptors and cause excessive release of
thyroid hormones
Treatment
 Carbimazole
 Iodine
 Propylthiouracil
Hypothyroidism
 Different in children and adults
 Called myxedema in adults
Characterised by:
 Edema of the larynx, people speak slowly and gain weight
 Skin becomes coarse and thick
 People who tend to be apathetic
 People who have yellowish skin: due to carotene, causing carotenemia (does not affect
eyes, to differentiate it from jaundice)
 High blood cholesterol, prone to myocardial infarction, cardiomyopathy
 People can have hypertension, can become obese
 Development of obstructive sleep apnoea (can cause hypertension)
 Coarse skin on the shins
Effects
 Hyperprolactinemia: can cause menorrhagia, sexual dysfunction
 Slow reflexes, slow relaxation phase
Causes in adulthood
 excessive intake of iodide: it can inhibit its own binding by Wolff-Chaikoff Effect
 Hashimoto’s thyroiditis
 Endemic goitres
 Grave's disease
 Prolonged use of anti-thyroid drugs
Causes in children
 Trisomy
Effects in children
Cretinism: short stature, slow mental development due to enzyme deficiency
Treatment
 Replacement of thyroid hormomes

Grave’s Disease
 Accounts for 60%-80% of cases of hyperthyroidism
 Antibodies against TSH receptor are produced
 Antibodies stimulate the receptor
18
  Produces marked T3 and T4 secretion and enlargement of thyroid gland (goitre)
 Due to long-loop negative feedback of T3 and T4, TSH secretion remains low
 Hallmark of disease: swelling of orbital tissues, producing protrusion of the eyeballs (e
xopthalmos), occurs in 50% of patients
 Antibodies to thyroglobulin and thyroid peroxidise are also produced
Hashimoto’s thyroiditis
 Autoimmune antibodies and infiltrating Killer T cells ultimately destroy the thyroid gla
nd
 During the end-stage, inflammation of thyroid causes excess thyroid hormone secretio
n and thyrotoxicosis similar to Graves Disease

ADRENAL GLANDS AND ENDORCINE PANCREAS

ADRENAL GLAND
 Consists of outer cortex and inner medulla
 Inner medulla secretes catecholamines
 Outer cortex secretes corticosteroids
 Cortical hormones: secreted by cortex. Are essential for life
 Glands also known as suprarenal glands
 Get blood supply directly from aorta or renal artery

Medulla
 Large less dense granules: secrete epinephrine
 Small very dense granules: secrete norepinephrine

Cortex
 Zona glomerulosa: secretes aldosterone, acts mainly on the kidney (affects sodium pot
assium pump)
 Zona fasciculata: secretes cortisol
 Zona reticulata/reticularis: secretes androgens
 Fetal adrenal cortex: produces sulfate conjugates of androgens which are converted t
o oestrogens by the placenta
 C19 steroids: androgen activity
 C21 steroids: mineralocorticoid or glucocorticoid activity
Cortical hormones
 Glucocorticoids: involved in glucose metabolism, eg cortisol and corticosterone
 Mineralocorticoids: involved in maintenance of sodium balance
 Adrenocortical secretion is controlled by ACTH
Cortisol
 Bound to corticosteroid-binding globulin (CBG)
 Increases in pregnancy, concentration falls during liver cirrhosis, multiple myeloma
 Can be administered to fetus in utero to stimulate maturation of surfactant
 Half life is 60 minutes
 90% in blood are bound to proteins (99.98% of thyroid hormones in blood are bound to
19
 protein)
 Metabolised in the liver
Metabolism
 Reduced to dihydrocortisol then tetrahydrocortisol
 Tetrahydrocortisol is conjugated to glucouronic acid
 17-ketosteroid derivatives of cortisol are formed then conjugated to sulfate then exc
reted in the urine

Glucocorticoids
 Have metabolic and non-metabolic effects
Metabolic:
 Make diabetes worse: exert an anti-insulin effect on peripheral tissues-increases bloo
d glucose levels
 Causes protein catabolism
 Increases gluconeogenesis
 Builds up stores of glycogen
 Increases activity of glucose 6 phosphatase (converts glucose 6 phosphate to glucose)
 Has anti insulin activities
 Has permissive effect on glucagon
 Reduces PNMT (converts norepinephrine to epinephrine) activity
 Increases number of free fatty acids: increases Lipolysis
 Increases ketone body formation in diabetes patients, but in normal patients, increase
in insulin provoked by rise in blood glucose obscures this action
 Permissive effects:must be present for glucagon and catecholamines to exert their cal
origenic effects, for catecholamines to exert their lipolytic effects, for catecholamin
es to produce pressor responses and bronchodilation
Non-metabolic effects
 Increases vascular reactivity
 In pharmacological doses, increases circulating platelets, neutrophils and RBCs, decrea
ses eosinophils, basophils and lymphocytes (help to alleviate allergies-it’s a steroid!)
 Inhibit phospholipase A2: inhibits Arachidonic acid metabolism
 Reduces production of cytoleukin 2
 Increases stability of lysosomes: reduces efficiency of leukocytes, helps autoimmune c
onditions but worsens bacterial infection
 Causes maturation of surfactant in the lungs (in fetal development)
 Inhibit ACTH secretion (long-loop negative feedback on the pituitary)
Control of secretion
 Cortisol: circadian rhythm, levels are low at night, increase between 4am and 10am, inc
rease due to stress and pain
 Negative feedback on anterior pituitary and hypothalamus

Aldosterone
 Is a Mineralocorticoid
 Major stimulus is angiotensin II through ACTH
20
  Half-life is about 20 minutes
Renin-angiotensin-aldosterone system:
 Angiotensin I liberated by action of renin on circulating angiotensinogen
 Angiotensin II formed from angiotensin I by action of angiotensin-converting enzyme/
carboxypeptidase/ACE in the lungs
 Renin secreted by juxtaglomerular apparatus of kidney
 Regulates Aldosterone via feedback mechanism
Stimuli which produce renin
 Are as a result of reduced volume or reduced sodium
 Low blood sodium
 Low blood flow
 Beta adrenergic stimulation through B1 receptors
Decreasing secretion
 ADH
 Aldosterone
 High sodium

Angiotensin II
 Has receptor type 1 and type 2
Effects
 Increases glomerular filtration
 Vasoconstriction
 Sodium Retention
 Growth factor to heart: remodelling of heart in cardiac failure. Cardiac cells replaced
by fibrous tissue, reducing contractility. ACE inhibitors given (lisinopril, enalapril)
 Increases secretion of Aldosterone
 Acts on subfornical organ of diencephalon to stimulate neural areas concerned with th
irst

Clinical Correlates of Glucocorticoids

Cushing Syndrome
 Prolonged increases in plasma glucocorticoids
 Can be ACTH-dependent or ACTH-independent
Causes of ACTH-independent
 Glucocorticoid-secreting adrenal tumours
 Adrenal hyperplasia
 Prolonged administration of exogenous glucocorticoids for diseases such as rheumatoid
arthritis
Causes of ACTH-dependent
 ACTH-secreting tumours of the anterior pituitary gland
 Tumours of other organs (eg lungs) that secrete ACTH (ectopic ACTH syndrome) or co
rticotrophin releasing hormone
Characterised by
 Protein-deficient patient
21
  Thin skin and superficial fascia
 Poorly developed muscles
 Minor injuries cause bruises and ecchymoses
 Poorly healing wounds
 Thin and scraggly hair
 Extremities are thin but fat accumulates in the abdominal wall, face, upper back (buff
alo hump)
 85% of the patients are hypertensive due to excessive action of mineralosteroids (incr
eased deoxycorticosterone secretion, increased angiotensionogen secretion, direct glu
cocorticoid effect on blood vessels)
 Osteoporosis: collapse of vertebral bodies, fractures
 Increased apetite
 Insomnia
 Euphoria and frank toxic psychoses
 potassium depletion (hyperalodosteronalism) and weakness of proximal muscles
 osteoporosis

ENZYME DEFICIENCIES
3B hydroxysteroid dehydrogenase
 Products are shunted to androgen production
 Causes incomplete closure of urethra in women
 Increased levels of DHEA: gives women male characteristics
21B hydroxylase
 Products are shunted to androgen production
 Decreased cortisol
 Increased androgens
 Salt loss in form of congenital hyperplasia
11B hydroxylase
 Products are shunted to androgen production
 Virilization: happens in women
 Water retention and hypertension, deoxycorticosterone is still produced→mineralocor
ticoid activity

Virilization
Characterised by
 Hirsuitism: excess hair in atypical places, eg facial hair
 Small breasts
 Occurs in females

HYPERALDOSTERONISM
 Excessive Aldosterone
 Primary: due to the adrenal gland
 Secondary: due to the pituitary
 Tertiary: due to the hypothalamus
22
Characterised by
 Weakness without edema
 Alkalosis responsible for tetany: reduced calcium
 Polyuria
 Secondary hyperaldosteronism

Adrenal insufficiency
 Commonest cause is Addison's disease
Features
 Weakness
 Lethargy
 Loss of apetite
 Inability to cope with stress
 Hyperpigmentation, due to excess ACTH (which can cause pigmentation) which is not b
eing inhibited by adrenal cortex hormones

ADRENAL MEDULLA
 Secretes catecholamines and opioids
 Major output is epinephrine
 PNMT: induced by glucocorticoids, produces adrenaline from noradrenaline
 Catecholamines have a half life of 2 min

Dopamine
 Has positive ionotropic effect
 Increases systolic pressure only
 Inhibits sodium potassium pump

Pheochromocytoma
 Adrenal medullary tumour which secretes catecholamines
 Produces constant hypertension, glucose in urine, extreme systolic hypertension
 Is the 10% tumour

ENDOCRINE PANCREAS
 Secretes insulin, glucagon, pancreatic polypeptide

Islets of Langerhans
 1 to 2 million in pancreas
 Alpha cells produce glucagon
 Beta cells produce insulin (are the most numerous in the islets)
 Delta cells produce somatostatin
 F cells produce polypeptide Y

Insulin
 Polypeptide containing two chains linked by disulfide bond. One chain also contains a di
23
 sulfide bond
 Gene on short arm of chromosome 11
 C peptide levels provide index of beta cell function (are supposed to be the same as ins
ulin levels)
Synthesis
 Comes from proinsulin
 A and B chains connected by c chain
 A and b chains are removed and form insulin
 C chain forms polypeptide C
 Half life is 5 minutes
 Binds to receptors and is internalised, destroyed by proteins in endosomes
 Receptor is tyrosine kinase
Regulation
 Important regulator in blood is glucose, enters B cells through GLUT2 transporters

Glucagon
 29 amino acid polypeptide
 Produced by alpha cells
 Only acts in the liver and adipose tissue
Actions
 Causes breakdown of glucose in the liver
 Causes gluconeogenesis

Hypoglycaemia
 Cholinergic, adrenergic, neuroglycopenic (sugar below 3)
 In order of decreasing glucose concentration
 Cholinergic: sweating
 Adrenergic: increased sympathetic discharge
 Neuroglycopenic: tremors, anger, frank psychoses, coma
Treatment
 Giving glucose

PINEAL GLAND
 Synthesises and secretes melatonin
 Communicates info about environmental lighting to the rest of the body
 Major function is to entrain biological rhythms

Structure
 Small, shaped like pine cone
 Not protected by the blood brain barrier (no blood brain barrier for endocrine glands)
 Composed of pinealocytes, glial cells, macrophages, mast cells
 In elder people, contains calcium deposits/corpora arenacea/brain sand (is normal) can
be seen on an X ray and can thus be used to tell if the two hemispheres are symmetric
 Have Beta receptors whose activity is increased by noradrenaline
24
  Retinohypothalamic fibres leaving eye synapse with suprachiasmatic nuclei of the hypo
thalamus
 Retina→hypothalamus→superior cervical ganglion→pineal gland (3 neuron system)
 Melatonin is synthesized from tryptophan
 Same way as serotonin but two more enzymes involved
 Enzyme activity is increased by increased sympathetic stimulation to pineal gland
 Transduces information from electrical impulse to chemicals: neuroendocrine transduc
er
Receptors for melatonin
 Type 1 and 2
 Mostly found in anterior pituitary, retina
Functions of melatonin
 Imposes synchronicity on cardiac rhythms
 Released during the night- circadian rhythm
 Controlled by genes : normal one is 26 hours without melatonin
 Important for sleep-wake cycle, people usually sleep during the night and are awake du
ring the day
 Also has apparent inhibitory effects on the thyroid and adrenal glands, inhibits secreti
on of gonadotrophins before puberty
 Light reduces its secretion

Clinical importance
 Is thought to be involved in motor neuron disease

ERYTHROPOETIN
 Increases synthesis of red blood cells
 Is a glycoprotein/cytokine
 Primary function is increasing the number of erythropoietin-sensitive cells determined
to become red blood cells
 Half life is 5min
 Produced mainly in the kidneys, 15% in the liver
 Produced by interstitial cells in peritubular capillary bed in the kidneys and by per
ivenous hepatocytes in the liver
 Brain produces all hormones, but they all have local functions (produces insulin which in
creases GLUT3 on astrocytes which produce lactate which is then taken up by brain an
d metablised- lactate shuttle)
Secretion stimulated by:
 Blood levels increased by anemia
 Alkalosis at high altitudes
 Adenosine and prostaglandins
Inhibition of secretion
 Oestrogens

HORMONES OF THE HEART AND NATRIURETIC PEPTIDES

25
  Secreted by the atria

Natriuretic peptides
 ANP first discovered in the atria: increase sodium loss in urine by increasing GFR, inhi
biting sodium reabsorption, inhibit renin secretion, antagonise vasopressor effects of
catecholamines
 ANP: atrial natriuretic peptide, causes natriuresis, secreted in reponse to hypervolemi
a
Receptors
 A and B use cGMP→ increases NO→ vasodilation in reponse to hypervolemia
 C thought to be clearance receptor
Secretion
 ANP in blood is usually 5fmol/L
 Levels are high in congestive heart failure, the failing heart will be so full of blood tha
t the atria will think there is hypervolemia
 Increased by: increased ECF volume, increase in sodium concentration
 BNP (brain natriuretic peptide) first discovered in the brain

BONE PHYSIOLOGY, CALCIUM AND PHOSPHATE METABOLISM

Regulation of Calcium Balance

 PTH, calcitonin, active Vitamin D
 Vitamin D: increases calcium absorption from intestine
 PTH: increases urinary excretion of phosphate, mobilises calcium from bone
 Calcitonin: increases absorption of calcium by bone from blood, inhibits resorption of b
one
 PTHrP: skeletal development in utero
 Estrogens,growth factors, insulin, glucocorticoids: also involved in bone development
 99%of calcium found in bone
 Total diffusable is 55%, total bound to protein is 45%
 Free ionised calcium is the one which is regulated: found free or bound in the ECF
 Calcium is absorbed by gut (through TRPV6 channels and a calcium dependent ATPase),
some involved in bone formation, some diffuses into ECF from bone resorption by oste
oclasts (release calcium into ECF), reabsorbed in the kidney by TRPV5 channels
Increasing calcium in blood:
 Increasing intake of calcium
 Increase bone resorption
 Affect its reabsorption in the kidneys
Functions of calcium
 Second messenger
 Blood clotting
 Important in secretion (exocytosis)
 Important for fertilisation (important for sperm motility)
26
  As a coenzyme
 Muscle contraction
 Neurons (exocytosis)

Implications of protein binding

 Measuring plasma protein is important in measuring plasma calcium
 Major binding protein is albumin
 ((40-[albumin])x0.02) + plasma [calcium]measured: finding the corrected calcium conce
ntration in plasma
 Total calcium is 70g/litre, albumin contributes 50% of it
 pH and ions affect protein binding
 An increase in H+ protein concentration: less calcium binds, protons compete with prot
eins for binding

Organs important in calcium balance

 Bone
 Kidneys
 GIT
 Skin
 Liver
Kidneys
 Large amounts of calcium are filtered
 60% reabsorbed in the proximal convoluted tubule
 Remainder absorbed in the ascending limb and distal convoluted tubule
 PTH regulates reabsorption in the distal tubule
 98-99% of calcium is reabsorbed
GIT
 Calcium absorbed through calcium dependent ATPase
 Regulated by activated Vitamin D (1,25 dihydroxycholecalciferol)
 Some absorption occurs by passive diffusion
 Absorption is high in states of low calcium intake
 High protein diet increases calcium absorption
 Decreased by oxalates, phosphates and alkalis which bind to calcium and stop it from b
eing absorbed

Phosphorus
 Found in ATP and many other compounds
 Total body phosphorus mirrors total body calcium
 85-90% is in the bone
 2 thirds is in organic compounds, 1 third is in inorganic compounds
 3mg exits bone, 3mg enters every day
 Absorbed mostly in the duodenum and jejunum
 Absorption is proportional to amount taken in
 Stimuli increasing calcium absorption also increase phosphorus absorption
27
Bone Physiology
 Bone is connective tissue
 Total blood flow to it is 200 to 400ml per minute
 Old bone is constantly being remodelled
 Bone is active
Functions of bone
 Phosphosphate and calcium homeostasis
 Rigidity supports loads and permits movement
 Protects vital organs

Bone growth
 Growth, modelling and remodelling under metabolic, mechanical and gravitational force
s
 Bone mass continues to increase until the 4th decade (30-39years of age)
 Women have lower peak bone mass
 Both males and females have age related loss of bone mass, more marked in females
 Can be modelled from cartilage then ossified (endochondral bone formation)
 Mesenchymal cells can form bone directly (intramembranous ossification)
 Width of the growth plate is proportional to the rate of growth: mainly affected by G
H and IGF1
 Bone age can be determined from looking at epiphyses, taking X rays of the skeleton (
non dominant hand): chronological age may not be the same as bone age

Epiphyseal closure
 Chondrocytes stop proliferating
 Become hypertrophic and secrete VEGF: leads to vascularisation and ossification of th
e plate
 Epiphyses close in an orderly temporal sequence

Bone formation and resorption

 Osteoclasts: resorb bone, release calcium into ECF
 Osteoblasts: produce new bone matrix
 Osteocytes: Maintain bone matrix, communicate with each other and blood vessels thr
ough cytoplasmic processes in canaliculi. Give important information for remodelling to
occur due to skeletal loading
Bone Remodelling
 When bone is resorbed and new bone is synthesized to replace it
 No periosteal remodelling, but in hyperthyroidism subperiosteal resorption is activated
 Osteoclasts and osteoblasts communicate with each other during remodelling through
coupling mediated by local signals eg osteoprotegrin, RANK ligand, MCSF, interferon g
amma
 Stromal cells, osteoblasts, activated T cells express RANK ligands on their cell memb
ranes and secrete MCSF (monocyte colony stimulating factor-a cytokine) which binds t
28
 o monocytes and causes them to differentiate
 Primarily under endocrine control
 PTH leads to bone resorption
 Oestrogens inhibit bone resorption, inhibit production of cytokines
 Hypercalcemia results from more osteoclastic activation than osteoblastic activity

RANK ligand
 Binds to RANK (receptor)
 Stimulates immature osteoclasts to mature
 Osteoprotegrin binds to RANK and inhibits osteoclasts
 Activated osteoclasts and stromal cells stimulate osteoclasts
 RANK ligand is a member of TNF ligands: increases synthesis of osteoclasts, makes m
ature osteoclasts resorb bone (thyroid, breast, lungs, prostate, ovaries, cervix, kidney
s cancers can move to bone stimulate bone resorption by releasing soluble RANK ligand
, activates osteoclasts only, not osteoblasts)
 Osteoprotegrin competes with RANK ligand for RANK receptor

Calcitonin inhibits osteoclasts

Prostaglandins activate osteoclasts

Bone Disease
 Osteopetrosis: osteoblasts more active than osteoclasts. Foramina in skulls blocked, c
ompressing nerves. Steady increase in bone density. Compact bone takes over spongy b
one, impeding blood cell formation
 Osteoporosis: osteoclasts more active, reduced bone mass. People prone to pathologic
fractures. Typically described in Colles fracture (dinnerfork deformity). Marked loss o
f bone mass. Fractures common in radius, vertebrae. Trabecular bone lost more rapidly
since it's more active
Causes of osteoporosis:
 Ageing: decrease in sex hormones
 Cushing’s syndrome- reduced production of interferon gamma (leads to excessive activ
ation of osteoclasts)
 Oestrogen deficiency leads to osteoporosis
Decreasing osteoporosis due to ageing
 Increased calcium
 Bisphosphonates
 Fluoride intake: stimulate osteoblasts
 Oestrogen replacement therapy

Control of calcium and phosphate homeostasis

Parathyroid Glands
 Derived from third (inferior ones) and fourth (superior ones) pharyngeal pouches
 Secrete PTH
PTH
29
  Has 84 amino acids
 Synthesized as part of 115 amino acids preproPTH
 Normal plasma level is 55 picograms/ml
 Half life is about 10min
 Kuppfer cells in liver cleave PTh
 34 AA residue is biologically active, the one measured is the 84 AA one
Effects
 In bone: increase osteoclastic activity
 Low levels given episodically increase bone formation
 Increases calcium reabsorption in distal tubule, increases phosphate excretion
 Excess causes acidosis, raising ionised calcium
 Activates 1 alpha hydroxylase in the kidneys (increases formation of active Vitamin D)
 In GIT: indirectly increases calcium absorption via active Vitamin D
 Acts through cAMP

Pseudohyperparathyroidism
 Hypoparathyroidism symptoms appear despite normal/elevated levels of PTH
 Calcium high, phosphate low
Two forms:
 Congenital disease: inactivity of Gs g-protein (so no increase in cAMP formation)
 cAMP formation normal, problem in kidney resulting in no effect from cAMP
 Treatment: give active Vitamin D

Regulation of PTH secretion

Increased by
 Low magnesium, low calcium: increases PTH. Chronically low levels of magnesium inhibit
PTH
 Beta adrenergic stimuli
Decreased by
 Active vitamin D

Hypoparathyroidism
 Causes Hypocalcemia, not enough calcium reabsorbed from kidneys and GIT, failure to
mobilise calcium from bone
 Causes hyperexcitabiliy
 No defect in blood coagulation
 Patients present with seizures, hypertension, heart disease (hypocalcemic cardiomyopa
thy), cataracts
Hyperparathyroidism
 Very difficult to diagnose
 Primary and tertiary forms result in high calcium levels in blood
 Kidney stones form: causes colicy pain
 Causes poor memory, dulled mentation, muscle weakness, sensory motor disturbances,
non-specific constipation
30
Calcium receptor mutations
 Loss of function: decreased negative feedback, leads to hypercalcemia (can be due to
release of PTHrP)

PTHrP
 Stimulates proliferation and mineralisation of cartilage in utero
 Inhibits excitotoxic damage to developing neurons
 Increases calcium transport in placenta
 May have role in eruption of teeth and development of breasts

Hypercalcemia of malignancy
 Perioral parasthesia caused by hypercalcemia

Vitamin D
 Needs light to be synthesized, can be synthesized in the skin when it is exposed to UV
 Synthesized from cholesterol, can be obtained from diet
 Can be synthesized
 In liver, is converted to 25 hydroxy Vitamin D

1-alpha hydroxylase
 Present in kidneys, macrophages, keratinocytes
Effects of vitamin D
 Increases synthesis of calbindin and calcium/hydrogen ATPase
 Increased reabsorption of calcium and phosphate in the kidneys-increases levels of gr
owth
 Thought to inhibit proliferation of skin cells- used to treat psoriasis
Effects on bone
 Deficiency leads to rickets in children, osteomalacia in adults
Regulation of synthesis of vitamin D
Increased by
 Increased PTH
 Low calcium
 Low phosphate
Decreased by
 Increased phosphate and calcium
 Decreased PTH
 Vitamin D (active metabolite)

Rickets and osteomalacia

 Rickety rosary: beads at costochondral joints

Vitamin D receptors
 People lacking vitamin D receptor results in alopecia totalis: no hair for life. Vitamin D
31
 may have a role in hair follicle maturation

Calcitonin
 Is a 32 AA peptide
 Secreted by parafollicular C cells (derived from the 5th pharyngeal pouch/the ultimobr
anchial body)
 Lowers calcium levels in blood
 Half life is less than 10min
Secretion increased by
 Beta agonists
 Dopamine
 Oestrogens
Effects
 Decreases calcium and phosphate levels in blood
 Causes mild natriuresis
 Famed for use in treatment of Paget's Disease of the bone, osteoporosis, hypercalcem
ia
Cortisol
 Decreases calcium levels: inhibiting osteoclasts formation and activity
 Increases renal excretion of calcium
 Inhibits protein synthesis
 Decreases calcium and phosphate absorption from GIT
 Can depress hypercalcemia of malignancy
Growth hormone
 Increases calcium absorption from GIT
Thyroid hormones in excess
 Can cause osteoporosis
 Can cause hypercalcemia
 People with hyperthyroidism can present with osteoporosis
Insulin
 Increases protein synthesis in bone
 Diabetic patients can have osteoporosis
 Increases phosphate reabsorption in proximal convoluted tubule
If a parathyroid gland is taken out, it can be put back in muscle. Blood supply will be re
-established and it will produce PTH. One of the symptoms of thyroid surgery is Hypoc
alcemia

Beta adrenergic stimuli increase secretion of

 Renin: through B1 receptors in the kidney
 Parathyroid hormone
 Calcitonin
 Melatonin: through B1 nordrenaline receptors in the pineal gland/epiphysis cerebri
 Angiotensin II: indirectly through increased renin secretion
 ADH: indirectly because of increased angiotensin II
32
33