Introduction to Endocrine Dr. Pandian M.

THIS PPT ONLY FIOR STUDY PURPOSE # MBBS#BDS#BPTH#ALLIED SCIENCES

1. Endocrine Physiology
Dale Buchanan Hales, PhD
Department of Physiology & Biophysics

2. Arnold A Berthold
(1803-1861)
•In one of the first endocrine
experiments ever recorded,
Professor Arnold A. Berthold of
Gottingen did a series of tests
on roosters in 1849 while he
was curator of the local zoo.

3. Ablation and replacement
•Bethold found that a rooster's comb is an
androgen-dependent structure. Following
castration, the comb atrophies, aggressive male
behavior disappears, and interest in the hens is
lost.
•Importantly, Berthold also found that these
castration-induced changes could be reversed by
administration of a crude testicular extract (or
prevented by transplantation of the testes).

4. Claude Bernard
(1813-1878)
Claude Bernard stated that the
endocrine system regulates the
internal milieu of an animal. The
“internal secretions” were
liberated by one part of the body,
traveled via the bloodstream to
distant targets cells. Circa 1854
Bernard's charge was to
demonstrate that medicine, in
order to progress, must be
founded on experimental
physiology.

5. Endocrine system maintains
homeostasis
The concept that hormones acting on distant target
cells to maintain the stability of the internal milieu
was a major advance in physiological
understanding.
The secretion of the hormone was evoked by a
change in the milieu and the resulting action on
the target cell restored the milieu to normal.
The desired return to the status quo results in the
maintenance of homeostasis

6. Charles Edouard Brown-Séquard
(1817-1894)
•Brown-Sequard further piqued mainstream
scientific interest in the chemical contents of the
testes with his famous auto-experimentation. On
June 1, 1889, before the Sociète de Biologic in
Paris, Brown-Sequard reported that he had
increased his physical strength, mental abilities and
appetite by self-injection with an extract derived
from the testicles of dogs and guinea pigs
•Although never substantiated, this claim prompted
researchers around the world to pursue the new field
of organotherapy

7. Ernest Henry Starling
(1866-1927)
•Besides "his" law of the heart, Starling discovered
the functional significance of serum proteins.
•In 1902 along with Bayliss he demonstrated that
secretin stimulates pancreatic secretion.
•In 1924 along with E. B. Vernay he demonstrated
the reabsorption of water by the tubules of the
kidney.
•He was the first to use the term hormone

8. Jim Ferguson
1947-2002
•Famous cardiovascular
physiologist
•Truly understood “Starling’s
Law”
•Disputed that the main
purpose of the cardiovascular
system was to deliver
hormones.

9. Sensing and signaling
Endocrine “glands”
synthesize and store
hormones. These glands
have a sensing and
signaling system which
regulate the duration and
magnitude of hormone
release via feedback from
the target cell.

10. Endocrine vs. Nervous System
•Major communication systems in the body
•Integrate stimuli and responses to changes
in external and internal environment
•Both are crucial to coordinated functions of
highly differentiated cells, tissues and
organs
•Unlike the nervous system, the endocrine
system is anatomically discontinuous.

11. Nervous system
•The nervous systemexerts
point-to-point control through
nerves, similar to sending
messages by conventional
telephone. Nervous control is
electrical in nature and fast.

12. Hormones travel via the
bloodstream to target cells
•The endocrine systembroadcasts its
hormonal messages to essentially all
cells by secretion into blood and
extracellular fluid. Like a radio
broadcast, it requires a receiver to get
the message -in the case of endocrine
messages, cells must bear a receptor
for the hormone being broadcast in
order to respond.

13. A cell is a target because is has a specific
receptor for the hormone
Most hormones circulate in blood, coming into contact with essentially
all cells. However, a given hormone usually affects only a limited
number of cells, which are called target cells. A target cell responds
to a hormone because it bears receptorsfor the hormone.

14. Principal functions of the
endocrine system
•Maintenanceoftheinternalenvironmentinthe
body(maintainingtheoptimumbiochemical
environment).
•Integrationandregulationofgrowthand
development.
•Control,maintenanceandinstigationofsexual
reproduction,includinggametogenesis,coitus,
fertilization,fetalgrowthanddevelopmentand
nourishmentofthenewborn.

15. Types of cell-to-cell signaling
Classic endocrinehormones
travel via bloodstream to
target cells; neurohormones
are released via synapses and
travel via the bloostream;
paracrinehormones act on
adjacent cells and autocrine
hormones are released and
act on the cell that secreted
them. Also, intracrine
hormones act within the cell
that produces them.

16. Response vs. distance traveled
Endocrine action: the hormone is distributed in blood and binds to
distant target cells.
Paracrine action: the hormone acts locally by diffusing from its
source to target cells in the neighborhood.
Autocrine action: the hormone acts on the same cell that produced
it.

17. Major hormones and systems
•Top down organization of endocrine system.
•Hypothalamus produces releasing factors that
stimulate production of anterior pituitary hormone
which act on peripheral endocrine gland to
stimulate release of third hormone
–Specific examples to follow
•Posterior pituitary hormones are synthesized in
neuronal cell bodies in the hypothalamus and are
released via synapses in posterior pituitary.
–Oxytocin and antidiuretic hormone (ADH)

18. Types of hormones
•Hormones are categorized into four
structural groups, with members of each
group having many properties in
common:
–Peptides and proteins
–Amino acid derivatives
–Steroids
–Fatty acid derivatives -Eicosanoids

19. Rangefrom3aminoacidstohundredsof
aminoacidsinsize.
Oftenproducedaslargermolecularweight
precursorsthatareproteolyticallycleavedto
theactiveformofthehormone.
Peptide/proteinhormonesarewatersoluble.
Comprisethelargestnumberofhormones–
perhapsinthousands
Peptide/protein hormones

20. Peptide/protein hormones
•Areencodedbyaspecificgenewhichistranscribedinto
mRNAandtranslatedintoaproteinprecursorcalleda
preprohormone
•Preprohormonesareoftenpost-translationallymodifiedin
theERtocontaincarbohydrates(glycosylation)
•Preprohormonescontainsignalpeptides(hydrophobic
aminoacids)whichtargetsthemtothegolgiwheresignal
sequenceisremovedtoformprohormone
•Prohormoneisprocessedintoactivehormoneand
packagedintosecretoryvessicles

21. Peptide/protein hormones
•Secretoryvesiclesmovetoplasmamembranewherethey
awaitasignal.Thentheyareexocytosedandsecretedinto
bloodstream
•In some cases the prohormone is secreted and converted in
the extracellular fluid into the active hormone: an example
is angiotensin is secreted by liver and converted into active
form by enzymes secreted by kidney and lung

22. Peptide/protein hormone synthesis

23. Amine hormones
There are two groups of hormones derived from the
amino acid tyrosine
Thyroid hormonesand Catecholamines

24. Thyroid Hormone
Thyroid hormonesare basically a "double" tyrosine with
the critical incorporation of 3 or 4 iodine atoms.
Thyroid hormone is produced by the thyroid gland and
is lipid soluble
Thyroidhormonesareproducedbymodificationofa
tyrosineresiduecontainedinthyroglobulin,post-
translationallymodifiedtobindiodine,thenproteolytically
cleavedandreleasedasT4andT3.T3andT4thenbindto
thyroxinbindingglobulinfortransportintheblood

25. Thyroid hormones

26. Catecholamine hormones
Catecholaminesare both neurohormones and
neurotransmitters.
These include epinephrine, and norepinephrine
Epinephrineandnorepinephrineareproduced
bytheadrenalmedullabotharewatersoluble
Secretedlikepeptidehormones

27. Synthesis of catecholamines

28. Amine Hormones
•Two other amino acids are used for
synthesis of hormones:
•Tryptophanis the precursor to serotonin
and the pineal hormone melatonin
•Glutamic acidis converted to histamine

29. Allsteroidhormonesarederivedfrom
cholesterolanddifferonlyinthering
structureandsidechainsattachedtoit.
Allsteroidhormonesarelipidsoluble
Steroid hormones

30. Types of steroid hormones
•Glucocorticoids; cortisol is the major
representative in most mammals
•Mineralocorticoids; aldosterone being
most prominent
•Androgenssuch as testosterone
•Estrogens, including estradiol and estrone
•Progestogens(also known a progestins)
such as progesterone

31. Steroid hormones
•Arenotpackaged,butsynthesizedand
immediatelyreleased
•Are all derived from the same parent compound:
Cholesterol
•Enzymes which produce steroid hormones from
cholesterol are located in mitochondria and
smooth ER
•Steroids are lipid soluble and thus are freely
permeable to membranes so are not stored in cells

32. Steroid hormones
•Steroid hormones are not water soluble so have to
be carried in the blood complexed to specific
binding globulins.
•Corticosteroid binding globulin carries cortisol
•Sex steroid binding globulin carries testosterone
and estradiol
•In some cases a steroid is secreted by one cell and
is converted to the active steroid by the target cell:
an example is androgen which secreted by the
gonad and converted into estrogen in the brain

33. Steroids can be transformed
to active steroid in target cell

34. Steroidogenic Enzymes
Common name "Old" name Current name
Side-chain cleavage enzyme;
desmolase
P450
SCC
CYP11A1
3 beta-hydroxysteroid
dehydrogenase
3 beta-HSD 3 beta-HSD
17 alpha-hydroxylase/17,20 lyaseP450
C17
CYP17
21-hydroxylase P450
C21
CYP21A2
11 beta-hydroxylase P450
C11
CYP11B1
Aldosterone synthase P450
C11AS
CYP11B2
Aromatase P450
aro
CYP19

36. Steroid hormone synthesis
All steroid hormones are derived from cholesterol.
A series of enzymatic steps in the mitochondria
and ER of steroidogenic tissues convert
cholesterol into all of the other steroid hormones
and intermediates.
The rate-limiting step in this process is the
transport of free cholesterol from the cytoplasm
into mitochondria.This step is carried out by the
Steroidogenic Acute Regulatory Protein (StAR)

37. Steroid hormone synthesis
•The cholesterol precursor comes from cholesterol
synthesized within the cell from acetate, from
cholesterol ester stores in intracellular lipid
droplets or from uptake of cholesterol-containing
low density lipoproteins.
•Lipoproteins taken up from plasma are most
important when steroidogenic cells are chronically
stimulated.

38. cholesterol
Extracellular
lipoprotein
Cholesterol
pool
LH
ATP
cAMP
PKA+
Pregnenolone
Progesterone
Androstenedione
TESTOSTERONE
3bHSD
P450c17
17bHSD
acetate

39. 1,25-dihydroxyVitaminD3isalsoderived
fromcholesterolandislipidsoluble
Notreallya“vitamin”asitcanbe
synthesizeddenovo
Actsasatruehormone
1,25-Dihydroxy Vitamin D3

40. Fatty Acid Derivatives -
Eicosanoids
•Arachadonic acid is the most abundant
precursor for these hormones.Stores of
arachadonic acid are present in membrane lipids
and released through the action of various lipases.
The specific eicosanoids synthesized by a cell are
dictated by the battery of processing enzymes
expressed in that cell.
•These hormones are rapidly inactivated by being
metabolized, and are typically active for only a
few seconds.

41. Fatty Acid Derivatives -
Eicosanoids
•Eicosanoidsare a large group of molecules
derived from polyunsaturated fatty acids.
•The principal groups of hormones of this
class are prostaglandins, prostacyclins,
leukotrienes and thromboxanes.

42. Regulation of hormone
secretion
Sensingandsignaling:abiologicalneedissensed,
theendocrinesystemsendsoutasignaltoatarget
cellwhoseactionaddressesthebiologicalneed.
Keyfeaturesofthisstimulusresponsesystemare:
receiptofstimulus
synthesisandsecretionofhormone
deliveryofhormonetotargetcell
evokingtargetcellresponse
degradationofhormone

43. Control of Endocrine Activity
•The physiologic effects of hormones depend
largely on their concentration in blood and
extracellular fluid.
•Almost inevitably, disease results when hormone
concentrations are either too high or too low, and
precise control over circulating concentrations of
hormones is therefore crucial.

44. Control of Endocrine Activity
The concentration of hormone as seen by target
cells is determined by three factors:
•Rate of production
•Rate of delivery
•Rate of degradation and elimination

45. Control of Endocrine Activity
Rate of production:Synthesis and secretion of
hormones are the most highly regulated aspect of
endocrine control. Such control is mediated by
positive and negative feedback circuits, as described
below in more detail.

46. Control of Endocrine Activity
Rate of delivery:An example of this effect is
blood flow to a target organ or group of target
cells -high blood flow delivers more hormone
than low blood flow.

47. Control of Endocrine Activity
Rate of degradation and elimination:Hormones,
like all biomolecules, have characteristic rates of
decay, and are metabolized and excreted from the
body through several routes.
Shutting off secretion of a hormone that has a very
short half-life causes circulating hormone
concentration to plummet, but if a hormone's
biological half-life is long, effective concentrations
persist for some time after secretion ceases.

48. Feedback Control of Hormone
Production
Feedback loops are used
extensively to regulate
secretion of hormonesin the
hypothalamic-pituitary axis.
An important example of a
negative feedback loop is seen
in control of thyroid hormone
secretion

49. Inputs to endocrine cells

50. Neural control
•Neural input to hypothalamus stimulates
synthesis and secretion of releasing factors
which stimulate pituitary hormone
production and release

51. Chronotropic control
•Endogenous neuronal rhythmicity
•Diurnal rhythms, circadian rhythms (growth
hormone and cortisol), Sleep-wake cycle;
seasonal rhythm

52. Episodic secretion of
hormones
•Response-stimulus coupling enables the
endocrine system to remain responsive to
physiological demands
•Secretory episodes occur with different
periodicity
•Pulses can be as frequent as every 5-10
minutes

53. •The most prominent episodes of release occur
with a frequency of about one hour—referred to as
circhoral
•An episode of release longer than an hour, but less
than 24 hours, the rhythm is referred to as
ultradian
•If the periodicity is approximately 24 hours, the
rhythm is referred to as circadian
–usually referred to as diurnalbecause the increase in
secretory activity happens at a defined period of the
day.
Episodic secretion of hormones

54. Circadian (chronotropic) control

55. Circadian Clock

56. Physiological importance of
pulsatile hormone release
•Demonstrated by GnRH infusion
•If given once hourly, gonadotropin secretion and
gonadal function are maintained normally
•A slower frequency won’t maintain gonad
function
•Faster, or continuous infusion inhibits
gonadotropin secretion and blocks gonadal steroid
production

57. Clinical correlate
•Long-acting GnRH analogs (such as
leuproline) have been applied to the
treatment of precocious puberty, to
manipulate reproductive cycles (used in
IVF), for the treatment of endometriosis,
PCOS, uterine leiomyoma etc

58. Feedback control
•Negativefeedbackismostcommon:forexample,
LHfrompituitarystimulatesthetestistoproduce
testosteronewhichinturnfeedsbackandinhibits
LHsecretion
•Positive feedback is less common: examples
include LH stimulation of estrogen which
stimulates LH surge at ovulation

59. Negative feedback effects of cortisol

60. Substrate-hormone control
•Glucose and insulin: as glucose increases it
stimulates the pancreas to secrete insulin

61. Feedback control of insulin by
glucose concentrations