IVMS Endocrine Secretion and Action I

Endocrine Glands:
Secretion and
Action of Hormones
IVMS Endocrinology 1 of 4
Marc Imhotep Cray, M.D.
BMS & ICM Professor/ USMLE Steps 1 & 2 Review Tutor

Correlative study / review:
Histology Endocrine Glands

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Endocrine
Learning Concepts Outline (1)
Normal processes
•embryonic development, fetal maturation, and perinatal changes
•organ structure and function
ohypothalamus, posterior and anterior pituitary gland
othyroid gland
oparathyroid glands
oadrenal cortex, adrenal medulla
opancreatic islets
oovary and testis
oadipose tissue
•cell/tissue structure and function, including hormone synthesis, secretion, action,
and metabolism
opeptide hormones
osteroid hormones, including vitamin D
othyroid hormones
ocatecholamine hormones
orenin-angiotensin system
•repair, regeneration, and changes associated with stage of life
2


Endocrine
Abnormal processes
•infectious, inflammatory, and immunologic disorders
•traumatic and mechanical disorders
•neoplastic disorders (including pituitary, thyroid, parathyroid, adrenal cortex,
pancreatic islets, neural crest, pheochromocytoma)
•metabolic and regulatory processes (including diabetes mellitus, pituitary,
hypothalamus, thyroid, parathyroid, pancreatic islet disorders, adrenal disorders)
•vascular disorders
•systemic disorders affecting the endocrine system
•idiopathic disorders
•degenerative disorders
•drug-induced adverse effects on the endocrine system
•congenital and genetic disorders affecting the endocrine system

3


Endocrine
Principles of therapeutics
•mechanisms of action and use of drugs for treatment of disorders of the
endocrine system
ohormones and hormone analogs
ostimulators of hormone production
oinhibitors of hormone production
ohormone antagonists
opotentiators of hormone action
oantiobesity agents
ononhormonal therapy for endocrine disorders
oother treatment for diabetes
•other therapeutic modalities

4


Endocrine

Gender, ethnic, and behavioral considerations affecting disease
treatment and prevention, including psychosocial, cultural,
occupational, and environmental

•emotional and behavioral factors
•influence on person, family, and society
•occupational and other environmental risk factors
•gender and ethnic factors

5


Endocrine Glands and Hormones

 Secrete biologically
active molecules into
the blood.
 Lack ducts.
 Carry hormones to
target cells that
contain specific
receptor proteins for
that hormone.
 Target cells can
respond in a specific
fashion.
6


Endocrine Glands and Hormones
(continued)

 Neurohormone:
 Specialized neurons that secrete chemicals into
the blood rather than synaptic cleft.
 Chemical secreted is called neurohormone.
 Hormones:
 Affect metabolism of target organs.
 Help regulate total body metabolism, growth, and
reproduction.

7


Chemical Classification of
Hormones

 Amines:
 Hormones derived from tyrosine and tryptophan.
 NE, Epi, T4.

 Polypeptides and proteins:
 Polypeptides:
 Chains of < 100 amino acids in length.
 ADH.
 Protein hormones:
 Polypeptide chains with > 100 amino acids.
 Growth hormone.

8


Hormones (continued)

 Lipids derived from cholesterol.
 Are lipophilic hormones.
 Testosterone.
 Estradiol.
 Cortisol.
 Progesterone.

9



10



 Glycoproteins:
 Long polypeptides (>100) bound to 1 or more
carbohydrate (CHO) groups.
 FSH and LH.
 Hormones can also be divided into:
 Polar:
 H20 soluble.
 Nonpolar (lipophilic):
 H20 insoluble.
 Can gain entry into target cells.
 Steroid hormones and T4.
 Pineal gland secretes melatonin:
 Has properties of both H20 soluble and lipophilic hormones.
11


Prohormones and Prehormones
 Prohormone:
 Precursor is a longer chained polypeptide that is
cut and spliced together to make the hormone.
 Proinsulin.
 Preprohormone:
 Prohormone derived from larger precursor
molecule.
 Preproinsulin.
 Prehormone:
 Molecules secreted by endocrine glands that are
inactive until changed into hormones by target
cells.
 T4 converted to T3.
12


Common Aspects of Neural and
Endocrine Regulation
 APs are chemical events produced by diffusion of
ions through neuron plasma membrane.
 Action of some hormones are accompanied by ion
diffusion and electrical changes in the target cell.
 Nerve axon boutons release NTs.
 Some chemicals are secreted as hormones, and also are
NTs.
 In order for either a NT or hormone to function in
physiological regulation:
 Target cell must have specific receptor proteins.
 Combination of the regulatory molecule with its receptor
proteins must cause a specific sequence of changes.
 There must be a mechanism to quickly turn off the action of
a regulator.
13


 Synergistic:
 Two hormones work together to produce a
result.
 Additive:
 Each hormone separately produces response,
together at same concentrations stimulate even
greater effect.
 NE and Epi.
 Complementary:
 Each hormone stimulates different step in the
process.
 FSH and testosterone.
14


Hormonal Interactions (continued)

 Permissive effects:
 Hormone enhances the responsiveness of a
target organ to second hormone.
 Increases the activity of a second hormone.
 Prior exposure of uterus to estrogen induces
formation of receptors for progesterone.

 Antagonistic effects:
 Action of one hormone antagonizes the effects
of another.
 Insulin and glucagon.

15


Effects of [Hormone] on Tissue
Response
 [Hormone] in blood reflects the rate of
secretion.
 Half-life:
 Time required for the blood [hormone] to be
reduced to ½ reference level.
 Minutes to days.
 Normal tissue responses are produced only
when [hormone] are present within
physiological range.
 Varying [hormone] within normal, physiological
range can affect the responsiveness of target
cells.
16


Effects of [Hormone] on Tissue
Response (continued)

 Priming effect (upregulation):
 Increase number of receptors formed on target
cells in response to particular hormone.
 Greater response by the target cell.
 Desensitization (downregulation):
 Prolonged exposure to high [polypeptide
hormone].
 Subsequent exposure to the same [hormone] produces
less response.
 Decrease in number of receptors on target cells.
 Insulin in adipose cells.

 Pulsatile secretion may prevent downregulation.

17


Mechanisms of Hormone Action
 Hormones of same chemical class have
similar mechanisms of action.
 Similarities include:
 Location of cellular receptor proteins depends
on the chemical nature of the hormone.
 Events that occur in the target cells.
 To respond to a hormone:
 Target cell must have specific receptors for
that hormone (specificity).
 Hormones exhibit:
 Affinity (bind to receptors with high bond strength).
 Saturation (low capacity of receptors).
18


Hormones That Bind to Nuclear
Receptor Proteins

 Lipophilic steroid and
thyroid hormones are
attached to plasma
carrier proteins.
 Hormones dissociate
from carrier proteins to
pass through lipid
component of the target
plasma membrane.
 Receptors for the
lipophilic hormones are
known as nuclear
hormone receptors.
19


Nuclear Hormone Receptors
 Steroid receptors are located in cytoplasm and in the
nucleus.
 Function within cell to activate genetic transcription.
 Messenger RNA directs synthesis of specific enzyme proteins
that change metabolism.
 Each nuclear hormone receptor has 2 regions:
 A ligand (hormone)-binding domain.
 DNA-binding domain.
 Receptor must be activated by binding to hormone
before binding to specific region of DNA called HRE
(hormone responsive element).
 Located adjacent to gene that will be transcribed.

20


Mechanisms of Steroid Hormone
Action

 Cytoplasmic receptor
binds to steroid
hormone.
 Translocates to nucleus.
 DNA-binding domain
binds to specific HRE of
the DNA.
 Dimerization occurs.
 Process of 2 receptor
units coming together at
the 2 half-sites.
 Stimulates transcription
of particular genes.
21


Mechanism of Thyroid Hormone
Action

 T4 passes into cytoplasm and
is converted to T3.
 Receptor proteins located in
nucleus.
 T3 binds to ligand-binding
domain.
 Other half-site is vitamin A
derivative (9-cis-retinoic)
acid.
 DNA-binding domain can
then bind to the half-site of
the HRE.
 Two partners can bind to
the DNA to activate HRE.
 Stimulate transcription of
genes.

22


Hormones That Use 2nd
Messengers

 Hormones cannot pass through plasma
membrane use 2nd messengers.
 Catecholamine, polypeptide, and glycoprotein
hormones bind to receptor proteins on the
target plasma membrane.
 Actions are mediated by 2nd messengers
(signal-transduction mechanisms).
 Extracellular hormones are transduced
into intracellular 2nd messengers.

23


Adenylate Cyclase-cAMP
 Polypeptide or glycoprotein hormone
binds to receptor protein causing
dissociation of a subunit of G-protein.
 G-protein subunit binds to and activates
adenylate cyclase.
 ATP cAMP + PPi
 cAMP attaches to inhibitory subunit of
protein kinase.
 Inhibitory subunit dissociates and
activates protein kinase.
24


Adenylate Cyclase-cAMP (continued)

 Phosphorylates
enzymes within the
cell to produce
hormone’s effects.
 Modulates activity of
enzymes present in
the cell.
 Alters metabolism of
the cell.
 cAMP inactivated by
phosphodiesterase.
 Hydrolyzes cAMP
to inactive
fragments.

25


Phospholipase-C-Ca2+

 Binding of Epi to a-adrenergic receptor
in plasma membrane activates a G-
protein intermediate, phospholipase C.
 Phospholipase C splits phospholipid into
IP3 and DAG.
 Both derivatives serve as 2nd messengers.
 IP3 diffuses through cytoplasm to ER.
 Binding of IP3 to receptor protein in ER
causes Ca2+ channels to open.

26


Phospholipase-C-Ca2+ (continued)

 Ca2+ diffuses into
the cytoplasm.
 Ca2+ binds to
calmodulin.
 Calmodulin
activates specific
protein kinase
enzymes.
 Alters the
metabolism of the
cell, producing
the hormone’s
effects.

27


Epi Can Act Through Two 2nd
Messenger Systems

28


Tyrosine Kinase

 Insulin receptor consists of 2 units that dimerize
when they bind with insulin.
 Insulin binds to ligand–binding site on plasma
membrane, activating enzymatic site in the cytoplasm.
 Autophosphorylation occurs, increasing tyrosine
kinase activity.
 Activates signaling molecules.
 Stimulate glycogen, fat and protein synthesis.
 Stimulate insertion of GLUT-4 carrier proteins.

29


Tyrosine Kinase (continued)

30


Pituitary Gland

 Pituitary gland is
located in the
diencephalon.
 Structurally and
functionally
divided into:
 Anterior lobe.
 Posterior lobe.

31


Pituitary Gland (continued)

 Anterior pituitary:
 Master gland (adenohypophysis).
 Derived from a pouch of epithelial tissue that
migrates upward from the mouth.
 Consists of 2 parts:
 Pars distalis: anterior pituitary.
 Pars tuberalis: thin extension in contact with the
infundibulum.
 Posterior pituitary(neurohypophysis):
 Formed by downgrowth of the brain during fetal
development.
 Is in contact with the infundibulum.
 Nerve fibers extend through the infundibulum.
32


Pituitary Hormones

 Anterior Pituitary:
 Trophic effects:
 High blood
[hormone] causes
target organ to
hypertrophy.
 Low blood
[hormone] causes
target organ to
atrophy.

33


Pituitary Hormones (continued)

 Posterior pituitary:
 Stores and releases 2 hormones that are
produced in the hypothalamus:
 Antidiuretic hormone (ADH/vasopressin):
 Promotes the retention of H20 by the kidneys.
 Less H20 is excreted in the urine.

 Oxytocin:
 Stimulates contractions of the uterus during parturition.
 Stimulates contractions of the mammary gland alveoli.
 Milk-ejection reflex.

34


Hypothalamic Control of
Posterior Pituitary

 Hypothalamus neuron
cell bodies produce:
 ADH: supraoptic
nuclei.
 Oxytocin:
paraventricular nuclei.
 Transported along
the hypothalamo-
hypophyseal tract.
 Stored in posterior
pituitary.
 Release controlled by
neuroendocrine
reflexes. 35


Hypothalamic Control of the
Anterior Pituitary

 Hormonal control rather
than neural.
 Hypothalamus neurons
synthesize releasing and
inhibiting hormones.
 Hormones are transported
to axon endings of
median eminence.
 Hormones secreted into
the hypothalamo-
hypophyseal portal
system regulate the
secretions of the anterior
pituitary

36


Feedback Control of the
Anterior Pituitary

 Anterior pituitary and hypothalamic secretions
are controlled by the target organs they
regulate.
 Secretions are controlled by negative feedback
inhibition by target gland hormones.
 Negative feedback at 2 levels:
 The target gland hormone can act on the
hypothalamus and inhibit secretion of releasing
hormones.
 The target gland hormone can act on the anterior
pituitary and inhibit response to the releasing
hormone.
37


Feedback Control of the
Anterior Pituitary (continued)

 Short feedback loop:
 Retrograde transport of
blood from anterior
pituitary to the
hypothalamus.
 Hormone released by
anterior pituitary
inhibits secretion of
releasing hormone.
 Positive feedback
effect:
 During the menstrual
cycle, estrogen
stimulates ―LH surge.‖

38


Higher Brain Function and
Pituitary Secretion

 Axis:
 Relationship between anterior pituitary and
a particular target gland.
 Pituitary-gonad axis.
 Hypothalamus receives input from
higher brain centers.
 Psychological stress affects:
 Circadian rhythms.
 Menstrual cycle.

39


Adrenal Glands

 Paired organs that cap the kidneys.
 Each gland consists of an outer cortex and
inner medulla.
 Adrenal medulla:
 Derived from embryonic neural crest
ectoderm (same tissue that produces the
sympathetic ganglia).
 Synthesizes and secretes:
 Catecholamines (mainly Epi but some NE).

40


Adrenal Glands (continued)

 Adrenal cortex:
 Does not receive
neural innervation.
 Must be stimulated
hormonally (ACTH).
 Consists of 3 zones:
 Zona glomerulosa.
 Zona fasciculata.
 Zona reticularis.
 Secretes
corticosteroids.

41


Functions of the Adrenal
Cortex

 Zona glomerulosa:
 Mineralcorticoids (aldosterone):

 Stimulate kidneys to reabsorb Na+ and secrete
K+.
 Zona fasciculata:
 Glucocorticoids (cortisol):

 Inhibit glucose utilization and stimulate
gluconeogenesis.
 Zona reticularis (DHEA):
 Sex steroids:

 Supplement sex steroids.
42


Cortex (continued)

43


Medulla

 Innervated by preganglionic
sympathetic axons.
 Increase respiratory rate.
 Increase HR and cardiac output.
 Vasoconstrict blood vessels, thus
increasing venous return.
 Stimulate glycogenolysis.
 Stimulate lipolysis.

44


Stress and the Adrenal
Gland

 Non-specific response
to stress produces the
general adaptation
syndrome (GAS).
 Alarm phase:
 Adrenal glands
activated.
 Stage of resistance:
 Stage of readjustment.
 Stage of exhaustion:
 Sickness and/or death
if readjustment is not
complete.

45


Thyroid Hormones

 Thyroid gland is located
just below the larynx.
 Thyroid is the largest of
the pure endocrine
glands.
 Follicular cells secrete
thyroxine.
 Parafollicular cells
secrete calcitonin.

46


Production of Thyroid
Hormones
 Iodide (I-) actively transported into the
follicle and secreted into the colloid.
 Oxidized to iodine (Io).
 Iodine attached to tyrosine within
thyroglobulin chain.
 Attachment of 1 iodine produces
monoiodotyrosine (MIT).
 Attachment of 2 iodines produces diiodotyrosine
(DIT).
 MIT and DIT or 2 DIT molecules coupled
together.
47



 T3 and T4 produced.
 TSH stimulates pinocytosis into the follicular
cell.
 Enzymes hydrolyze T3 and T4 from
thyroglobulin.
 Attached to TBG and released into blood.

48



49


Actions of T3

 Stimulates protein synthesis.
 Promotes maturation of nervous system.
 Stimulates rate of cellular respiration by:
 Production of uncoupling proteins.
 Increase active transport by Na+/K+ pumps.
 Lower cellular [ATP].
 Increases metabolic heat.
 Increases metabolic rate.
 Stimulates increased consumption of glucose, fatty
acids and other molecules.

50


Diseases of the Thyroid
 Iodine-deficiency
(endemic) goiter:
 Abnormal growth of
the thyroid gland.
 In the absence of
sufficient iodine,
cannot produce
adequate amounts of
T4 and T3.
 Lack of negative
feedback inhibition.
 Stimulates TSH,

which causes
abnormal
growth.

51


Diseases of the Thyroid (continued)

[Iodine-deficiency (endemic) goiter—continued]

 Adult myxedema:
 Accumulation of mucoproteins and fluid in subcutaneous tissue.
 Symptoms:
 Decreased metabolic rate.
 Weight gain.
 Decreased ability to adapt to cold.
 Lethargy.

 Grave’s disease:
 Autoimmune disorder:
 Exerts TSH-like effects on thyroid.
 Not affected by negative feedback.
 Cretinism:
 Hypothyroid from end of 1st trimester to 6 months postnatally.
 Severe mental retardation. 52


Parathyroid Glands

 Embedded in the lateral
lobes of the thyroid gland.
 Parathyroid hormone (PTH):
 Only hormone secreted by
the parathyroid glands.
 Single most important
hormone in the control of
blood [Ca2+].
 Stimulated by decreased
blood [Ca2+].
 Promotes rise in blood [Ca2+]
by acting on bones, kidney
and intestines.

53


Pancreatic Islets (Islets of
Langerhans)

 Alpha cells secrete glucagon.
 Stimulus is decrease in
blood [glucose].
 Stimulates glycogenolysis
and lipolysis.
 Stimulates conversion of
fatty acids to ketones.
 Beta cells secrete insulin.
 Stimulus is increase in blood
[glucose].
 Promotes entry of glucose
into cells.
 Converts glucose to
glycogen and fat.
 Aids entry of amino acids
into cells.
54


Pineal Gland

 Secretes melatonin:
 Production stimulated by the suprachiasmatic nucleus (SCN)
in hypothalamus.
 SCN is primary center for circadian rhythms.
 Light/dark changes required to synchronize.
 Melatonin secretion increases with darkness and peaks in
middle of night.
 May inhibit GnRH.
 May function in the onset of puberty (controversial).

55


Pineal Gland (continued)

56


Thymus

 Site of production of T cells (thymus-
dependent cells), which are lymphocytes.
 Lymphocytes are involved in cell-mediated
immunity.
 Secretes hormones that are believed to
stimulate T cells after leave thymus.
 Thymus gland size is large in newborns and
children.
 Regresses after puberty and becomes
infiltrated with strands of fibrous tissue.

57


Gonads and Placenta

 Gonads (testes and ovaries):
 Secrete sex hormones.
 Testosterone.
 Estradiol 17-b.
 After menopause, produces estrone.
 Progesterone.
 Placenta:
 Secretes large amounts of estriol,
progesterone, hCG, hCS.

58


Autocrine and Paracrine
Regulation

 Autocrine:
 Produced and act within the same tissue of an organ.
 All autocrine regulators control gene expression in target cells.
 Paracrine:
 Produced within one tissue and regulate a different tissue of
the same organ.
 Cytokines (lymphokines):
 Regulate different cells (interleukins) .
 Growth factors:
 Promote growth and cell division in any organ.
 Neutrophins:
 Guide regenerating peripheral neurons.

59


Prostaglandins
 Most diverse group of autocrine regulators.
 Produced in almost every organ.
 Wide variety of functions.
 Different prostaglandins may exert antagonistic
effects in some tissues.
 Immune system:
 Promote inflammatory process.
 Reproductive system:
 Play role in ovulation.
 Digestive system:
 Inhibit gastric secretion.

60


Prostaglandins (continued)

61


Prostaglandins (continued)

 Respiratory system:
 May bronchoconstrict or bronchodilate.
 Circulatory system:
 Vasoconstrictors or vasodilators.
 Urinary system:
 Vasodilation.
 Inhibitors of prostaglandin synthesis:
 Non-steroidal anti-inflammatory drugs (NSAIDS).
 Aspirin, indomethacin, ibuprofen: inhibit COX1.
 Celecoxib and rofecoxib: inhibit COX2.

62


ENDOCRINOLOGY HYPERLINK
Photos, Images and Pictures
 Atlas of the Endocrine System [Peyrin et Vandroux] - Univ de St.Etienne
(FR)
 Endocrine Pathol. images - U of Pittsburg
 Endocrine Pathol. index [EC Klatt] Some
 Pictures and illustrations in Endocrinology - Univ of Houston (US) Some
 Images in Endocrinology - MedStudents (BR) Advanced
 Imaging of the Diabetic Foot and Its Complications [A Gentili] - UCSD
 Images related to the Endocrine System - Cushings-Help.com A collection
of
 Thyroid surgery images from the American Thyroid Clinic Some
 Images of Thyroid Disorders [DW Gardner]
 Thyroid Imaging .com [G Perrella]

63

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