Lecture 9

HUMORAL REGULATION OF VISCERAL FUNCTIONS

ROLE OF ENDOCRINE GLANDS IN REGULATION OF
GROWTH AND DEVELOPMENT,
HOMEOSTASIS AND ADAPTATION
Розробник: к. біол. н., доцент І.С. Кармазіна
Затверджено на засіданні № 1 кафедри фізіології
1
від 28.08.2020
 LECTURE OUTLINE
1. Comparison of nervous and endocrine systems.
Intercommunication of neural and humoral regulation
2. Circuit of humoral regulation.
3. Factors of humoral regulation: structure, classification
4. Hormone receptors of and mode of their action:
membrane receptors, intracellular receptors, second
messengers, G-proteins, their role
5. Hypothalamo-hypophyseal system:
1) functional communication of hypothalamus and
hypophysis
2) releasing- and inhibitory factors of hypothalamus –
liberins and statins
3) neurosecretions of hypothalamus – ADH, oxytocin,
6. Effector endocrine glands and their hormones
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 Humoral regulation is the type of biological regulation which
provides information transmission by means of biological active
chemical compounds that travel in organism by way of blood and
lymph, as well as by diffusion into extracellular fluid.
Humoral regulation is realized by the endocrine system.
Endocrine system is a totality of all endocrine cells of an organism
that are able to produce humoral factors.
Endocrine system of human comprises following structures:
1) hypophysis,
1) Endocrine glands (glands of internal secretion) – 2) epiphysis,
specialized organs which main functions are synthesis 3) thyroid gland,
and secretion of hormones 4) parathyroid gland,
5) adrenal glands.

1) pancreas,
2) Portions of tissue and individual cells performing 2) sexual glands,
endocrine function as well as other functions: 3) hypothalamus and
other regions of CNS,
4) thymus,
5) organs of GIT,
6) kidney, 3
7) heart.
 Main function of hormones and endocrine system is
humoral regulation of wide spectrum of physiological processes

• Regulation of metabolism and maintenance of

homeostasis
Adrenaline enhances glycogen hydrolysis in liver and skeletal muscles
Thyroid hormones enhance metabolic rate in all cells
• Adaptation of visceral organs functions to
physical and mental activities
Adrenaline increases heart rate, blood circulation in the brain during
physical and mental loading
• Growth and development
Sexual hormones influence to the growth of the body and development
of secondary sexual characteristics
• Sensitivity of cells to other hormones
Glucocorticoids increases sensitivity of tissues to the adrenaline
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 Comparison of nervous and endocrine systems
Neuronal Regulation - Nervous System Humoral regulation - Endocrine System
Communicates by means of electrical impulses Communicates by means of chemical
and neurotransmitters compounds - hormones
Releases neurotransmitters into synapses at Releases hormones into bloodstream for
specific target cells general distribution throughout the body
Usually has relatively local, specific effect Sometimes has very general widespread effects
Excitation transmission rate is very high. Reacts Reacts more slowly to stimuli. The rate of
quickly to stimuli. blood flow in capillaries is about 0,03 m/sec.
Response is usually within 1 to 10 msec Response often taking from seconds to days (or
even months)
Stops quickly when stimulus ceases May continue responding long time after
stimulus stops
Adapts relatively quickly to continual Adapts relatively slowly; may continue
stimulation responding for days to weeks of stimulation

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 Principle circuit of humoral regulation
DIRECT CHANNEL
FROM CONTROLLING
HYPOTHALAMUS SENSOR + DEVICE
(receptor) (endocrine gland)
CHANNEL OF
EXTERNAL
COMMUNICATION

COMMUNICATION
Biological
Active

FEED-BACK
Substances

DIRECT CHANNEL OF
COMMUNICATION ORGAN-EFFECTOR

REGULATED
HOMEOSTATIC
PARAMETERS
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 Components of circuit of humoral regulation
• Channel of external communication – concentration of chemical
compounds or hormones that are regulated by the endocrine gland
• Direct channel from hypothalamus – hypothalamus as higher center
of humoral regulation can alter the functional activity of endocrine
glands
• Detectors – receptors of incretory cells membranes
• Controlling device – endocrine gland which receives information
about regulated homeostatic parameters
• Biological active substance – hormone circulating in the
bloodstream
• Organ-effector – is enable to change (↑ or ↓) the regulated
parameter when it is stimulated by hormone
• Regulated homeostatic parameter – parameter of internal
environment which is kept as constant or changed due to the
humoral regulation

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 There are 4 ways for humoral factors transmission:
1) Mediators way – humoral factor is released into the
synaptic cleft and acts as neurotransmitter (adrenaline,
serotonin)
2) Endocrine way - endocrine cells release their hormones
into the surrounding tissue fluid, and then the
bloodstream quickly picks up and distributes the
hormones. So, humoral factors act via the blood and
lymph (all true hormones)
3) Paracrine way – humoral factor acts to the neighboring
cells at of the same organ (some gastrointestinal
hormones, prostaglandins)
4) Neurocrine way – is supplied by the neuropeptides. These
are synthesized in the hypothalamus (encephalin,
endorphin, ADH, releasing-factors) and in many cells
diffusely located in the organism (substance P,
vasoactive peptide VAP, somatostatin).

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Classification of humoral factors according their origin
and physiological effects

HUMORAL FACTORS
are biological active substances

HORMONES METABOLITES

TRUE TISSUE Physiologic Pathologic

HORMONES HORMONES metabolites metabolites

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True hormones are synthesized by endocrine glands. They
interact with target cells and have widespread effects
• Liberins and statins of hypothalamus
• Tropic hormones of adenohypophysis
• Hypothalamo-hypophyseal hormones (oxytocin and ADH)
• Hormones of peripheral endocrine glands (adrenal cortex
and adrenal medulla, thyroid and parathyroid glands,
pancreas, sexual glands)
• Neuropeptides and amino acids of hypothalamus
(encephalin, endorphin, histamine, serotonin, etc.)
• Hormones of GIT & pancreas
• Components of renin-angiotensin system

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Tissue hormones are produced by different
unspecialized cells

• Components of kallikrein-kinin system

• Cytokines
• Natriuretic peptide
• Endothellin
• Nitrogen oxide (NO)

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 METABOLITES

Physiologic Pathologic
are produced by any cells of are produced by any cells of an
an organism especially during organism in pathological
their intensive work conditions
• CO2 • Hypoxia – deficiency of O2
• Hypercapnia – excess of CO2
• Lactic acid
• Hyperkalemia – excess of K+
• Pyruvic acid
• Hyperosmia – excess of
• Adenosine osmotic active substances
(Na+, Cl-, Glucose)

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 CHEMICAL CLASSIFICATION OF HORMONES
Chemical structure Example
Steroid hormones • sex steroids (estrogens, progesterone, and
are derivative testosterone)
substances of • corticosteroids of the adrenal gland (cortisol,
cholesterol corticosterone, aldosterone, and
dihydroepiandrosterone - DHEA)
Proteins and • anterior and posterior pituitary gland (OT, ADH,
polypeptides tropic hormones)
• hypothalamus (releasing and inhibitory factors)
• pancreas (insulin and glucagon),
• parathyroid gland (parathyroid hormone)

Monoamines • thyroid glands (thyroxine and triiodothyronine)

(biogenic amines) • adrenal medullae (epinephrine and
are derivative norepinephrine).
substances of amino
acid tyrosine
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 CLASSIFICATION OF HORMONES ACCORDING THEIR
PHYSIOLOGICAL ROLE

Function Hormones
Regulation of GH
growth and Thyroid hormones (T3, T4)
development estrogens and androgens

Regulation of Insulin, Glucagon (glucose concentration)

homeostasis Aldosteron, vasopressin, ANP (water-salt
balance);
Calcitonin, PTH (calcium metabolism);

Stress adaptation Catecholamines

Glucocorticoids
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 Biorhythms
• Most endocrine functions show both circadian
(approximately 24 hours) and ultradian (are found
within a circadian) rhythms (the light/dark cycles);
• They are controlled by the suprachiasmatic nuclei (are
in the anterior hypothalamus, on both sides of the
third cerebral ventricle and just above the optic
chiasm);
• Neurons in these nuclei show an intrinsic 24-hour
rhythmical pattern in both their metabolic and
electrical activities
• This pattern is modulated by inputs from many brain
regions as well as from the retina;
• it can be reset by neuropeptide Y or melatonin 15
 Hormone Receptors and Mode of Their Action
Hormones stimulate only those cells that have receptors for them!
The receptors are protein or glycoprotein molecules located on the
plasma membrane, on mitochondria and other organelles in the
cytoplasm, or in the nucleus.
• A target cell usually has a few thousand receptors for a given
hormone.
• Receptor-hormone interactions are similar to the enzyme-substrate
interactions. Unlike enzymes, receptors do not chemically change
their ligands, but they do exhibit enzyme-like specificity and
saturation.
• Specificity means that the receptor for one hormone will not bind
other hormones.
• High affinity – high strength of bond in the complex receptor-
hormone
• Saturation is the condition in which all the receptor molecules are
occupied by hormone molecules. Adding more hormone cannot
produce any greater effect.
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 Principles of receptors localization
The location of a hormone’s receptor proteins in its target
cells depends on the chemical nature of the hormone.
• The water-soluble hormones (catecholamines,
polypeptides, and glycoproteins) cannot pass through the
plasma membrane, so their receptors are located on the
outer surface of the membrane. In these cases, hormone
action requires the activation of second messengers
within the cell.
• The lipophilic hormones (steroids and thyroxine) can
pass through the plasma membrane and enter their
target cells. The receptor proteins for lipophilic
hormones are located within the cytoplasm and
nucleus.

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Difference between lipid- and water-soluble hormones
Lipid-soluble hormones Water-soluble hormones
(steroids, thyroid hormones) (peptides, proteins)
Receptors Inside the cell, Outer surface of the
usually in nucleus cell membrane
Intracellular Stimulates synthesis • Production of second messengers,
action of specific new proteins e.g., cAMP
• Insulin activates membrane-bound
tyrosine kinase
• Second messengers modify action of
intracellular proteins (enzymes)
Storage Synthesized as needed Stored in vesicles
Exception: thyroid In some cases, prohormone stored in
hormones vesicle along with an enzyme that splits
off the active hormone
Plasma Attached to proteins that serve as Dissolved in plasma (free, unbound)
transport carriers
Exception: adrenal androgens
Half-life Long (hours, days) Short (minutes)
ex: to affinity for protein carrier ex: to molecular weight
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 The mechanism of water-soluble hormones action
When hormones bind to
membrane receptor proteins,
they must activate specific
proteins in the plasma
membrane in order to produce
the second messengers required
to exert their effects.
Second-messenger systems that
involve the activation of
intracellular enzymes:
AC = adenylate cyclase; 1) tyrosine kinase (insulin, GH, Prolactin)
cAMP = cyclic adenosine 2) adenylate cyclase – ACTH, FSH, LH, PTH, TSH,
Glucagon, Calcitonin, Catecholamines
monophosphate;
3) phospholipase C – ADH, LHRH, TRH,
cGMP = cyclic guanosine Oxytocin, Catecholamines,
monophosphate;
4) Guanylate cyclase
DAG = diacylglycerol;
5) Receptor is connected with an ion channel
PLC = phospholipase C. 19
 The adenylate cyclase – cyclic AMP second-messenger system

1) The hormone binds to its receptor in the plasma

membrane of the target cell
2) This causes the dissociation of G-proteins,
allowing the free α-subunit to activate adenylate
cyclase
3) This enzyme catalyzes the production of cAMP
4) cAMP removes the regulatory subunit from
proteinkinase
5) Active protein kinase phosphorylates other
enzyme proteins, activating or inactivating
specific enzymes and thereby producing the
hormonal effects on the target cell 20
The phospholipase C – calcium second-messenger system

1) The hormone binds to its receptor in the plasma membrane of its target cell
2) Complex “hormone-receptor” causes the dissociation of G-proteins
3) G-protein subunit travels through the plasma membrane and activates phospholipase C, which
catalyzes the breakdown of a particular membrane phospholipid into diacylglycerol (DAG) and
inositol triphosphate (IP3)
4) IP3 enters the cytoplasm and binds to receptors in the endoplasmic reticulum, causing the
release of stored Ca2+. The Ca2+ then diffuses into the cytoplasm, where it acts as a second
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messenger to promote the hormonal effects in the target cell.
 Tyrosine kinase second-messenger system

The insulin receptor consists of two parts, each containing a beta polypeptide chain that spans the
membrane, and an alpha chain that contains the insulin-binding site
a) When two insulin molecules bind to the receptor, the two parts of the receptor phosphorylate each
other
b) This greatly increases the tyrosine kinase activity of the receptor
c) The activated receptor tyrosine kinase then phosphorylates a variety of “signal molecules” that
produce a cascade of effects in the target cell. 22
 The mechanism of steroid hormone action
1) Steroid hormones, transported
bound to plasma carrier proteins,
dissociate from their plasma
carriers and pass through the
plasma membrane of their target
cell
2) The steroid hormone binds to
receptors, which is in the cytoplasm
3) The hormone-bound receptor is
translocated to the nucleus, where
it binds to DNA
4) This stimulates genetic
transcription, resulting in new
mRNA synthesis
5) The newly formed mRNA codes for
the production of new proteins,
6) Proteins alter the metabolism of
target ell – the hormonal effects

Estrogen, for example, stimulates cells of the uterine lining to synthesize proteins that act as
progesterone receptors. Progesterone, which comes later in the menstrual cycle, then binds to these
receptors and stimulates the cells to produce enzymes that synthesize glycogen. Glycogen prepares the
uterus to nourish an embryo in the event of pregnancy. 23
 The mechanism of thyroid hormone action
1) Thyroxine (T4), carried to the
target cell, bound to its plasma
carrier protein, dissociates from
its carrier and passes through
the plasma membrane of its
target cell
2) In the cytoplasm, T4 is converted
into T3 (triiodothyronine), which
uses binding proteins to enter
the nucleus
3) The hormone-receptor complex
binds to DNA stimulating the
synthesis of new mRNA.
4) The newly formed mRNA codes
for the synthesis of new
proteins, which
5) produce the hormonal effects in
the target cell.

One of the proteins produced under the influence of T3 is Na+/K+ ATPase. One of the functions of
Na+-K+ ATPase is to generate heat, thus accounting for the calorigenic effect of thyroid hormone
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Hypothalamo-hypophyseal system
1. Hypothalamus

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 Hypothalamo-hypophyseal system
2. The pituitary gland
The pituitary gland (hypophysis) is
suspended from the hypothalamus
by a stalk and housed in the sella
turcica of the sphenoid bone.
• The pituitary gland consists of
three lobes:
• anterior (adenohypophysis),
• posterior (neurohypophysis),
• intermediate (pars intermedia –
in human adults is rudimentary
only);
• Hypothalamic control over
pituitary function is
accomplished through nervous
as well as circulatory pathways. 26
Hypothalamic Control of the Anterior Pituitary
• The basal portion of the
hypothalamus, known as the
median eminence, contains blood
capillaries that are drained by
venules in the stalk of the
pituitary.
• The vascular link between the
hypothalamus and the anterior
pituitary is called the
hypothalamo-hypophyseal portal
system.
• Regulatory hormones are secreted
into the hypothalamo-hypophyseal
portal system by neurons of the
hypothalamus.
• These hormones regulate the
secretions of the anterior pituitary
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 Hypothalamic-Anterior Pituitary System
• Secretory neurons located in the
paraventricular, arcuate and preoptic nuclei
of hypothalamus
• Their nerve endings all come together in the
median eminence region of the
hypothalamus
• The action potentials in the axons of the
secreting neurons of the hypothalamus
cause the release their hormones
• The release-promoting or –inhibiting
hormones are secreted into the hypophy-
seal portal system and transported to the
anterior pituitary, where exert their effects
on cells in the anterior and intermediate
lobes of the pituitary.

ArcN = arcuate nucleus;

PVN = paraventricular nucleus;
SON = supraoptic nucleus.
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 Effect of Hypothalamic Hormones on Anterior Pituitary
Hypothalamic Hormone Pituitary Target Principle effect

TRH Thyrotrophs + TSH and PRL secretion

Thyrotropin-releasing hormone (10%)
CRH Corticotrophs + ACTH secretion
Corticotropin-releasing hormone (10-25%)
GnRH Gonadotrophs +FSH and LH secretion
Gonadotropin-releasing hormone (10-15%)
PRH: Lactotrophs + PRL secretion
Prolactin-releasing hormone (10-15%)
PIH (dopamine) – PRL secretion
Prolactin-inhibiting hormone
GHRH Somatotrophs + GH secretion
Growth hormone–releasing (50%)
hormone
Somatostatin – GH and TSH secretion
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“+” – stimulation; “–” - inhibition
 Hormones of Anterior Pituitary
Hormone Target Organ Principle Effect

Anterior pituitary – 6 principle hormones

FSH: Follicle- Ovaries, Female: growth of ovarian follicles and secretion of
stimulating hormone testes estrogen
Male: sperm production (Sertoli’s cells)

LH: Luteinizing Ovaries, Female: ovulation, maintenance of corpus luteum

hormone testes Male: testosterone secretion (Leydig cells)
TSH: Thyroid- Thyroid gland Growth of thyroid, secretion of thyroid hormone
stimulating hormone
ACTH: Adrenal Growth of adrenal cortex, secretion of corticosteroids
Adrenocorticotropic cortex
hormone

GH: Growth hormone Liver Somatomedin secretion, widespread tissue growth

(somatotropin)

PRL: prolactin Mammary Female: milk synthesis

glands, testes Male: increase LH sensitivity and testosterone
secretion
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31
 Control the secretion rates of the
hypothalamus and the pituitary gland
• Hormone secretion is typically
controlled through negative feedback
• In the common, the hypothalamus
produces a releasing hormone (or
factor) that triggers the release of a
hormone by the anterior lobe of the
pituitary gland
• The pituitary hormone stimulates
release of a second hormone by the
target organ
• This second hormone suppresses
secretion of both the hypothalamic
releasing hormone and the pituitary
hormone.
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33
Hypothalamic Control of Posterior Pituitary

Posterior pituitary hormones are

actually produced in neuron cell bodies
of the hypothalamus :
• arginin vasopressin (ADH) and
oxytocin are synthesized in cells of
the magnocellular divisions of the
supraoptic and paraventricular
nuclei of the hypothalamus
• The hormones are transported
along axons of the hypothalamo-
hypophyseal tract to the posterior
pituitary, where they are stored
and later released.
The release of ADH and oxytocin from
the posterior pituitary is controlled by
neuroendocrine reflexes.

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 Antidiuretic hormone (ADH, Vasopressin)
• ADH is a major controller of water excretion and ECF
volume. ADH also controls osmolarity.
• The osmoreceptor neurons in the hypothalamus are
extremely sensitive and are able to maintain ECF
osmolarity within a very narrow range.
• Volume receptors are less sensitive than
osmoreceptors and a change of 10-15% in volume is
required to produce a measurable change in ADH.
• Vasopressin has two major actions, both mediated by
G protein–coupled receptors:
1. V1 - brain and in vascular smooth muscle.
• in the brain leads to increased drinking (possibly in
synergy with angiotensin II)
• in vascular smooth muscle causes vasoconstriction (by
increase in cytosolic Ca++).
2. V2 - renal collecting tubule
• insertion of water channels (aggrephores) into these
cells by a cAMP-dependent mechanism increasing
water permeability
• ↑ reabsorption at this site thus regulating body fluid
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osmolarity and body fluid volume.
Neural control of ADH secretion

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 Regulation of vasopressin secretion
• Osmoreceptors: are neurons that respond to increased plasma
osmolarity, principally plasma sodium concentration.
• Stretch mechanoreceptors: sensors for blood volume are located
near the junctions of the great veins with the left or right cardiac
atria.
• Osmoreceptors synapse with neurons of the SO and PVN and
stimulate them to secrete ADH from the posterior pituitary.
• The SO and PVN also receive input from cardiopulmonary
mechanoreceptors, as well as arterial baroreceptors.
• High blood volume or blood pressure tends to inhibit secretion
of ADH.
• Secretion of ADH is most sensitive to plasma osmolarity (1 %);
however, if blood volume decreases by 10% (such as
hemorrhage) or cardiac output falls, high levels of ADH are
secreted even if it causes abnormal plasma osmolarity.

• Alcohol: Alcohol inhibits vasopressin secretion causing increased

urine flow and is responsible for the dehydration that is part of a
morning hangover. 37
 Diabetes insipidus
• Results from the lack of an effect of ADH on the renal collecting
ducts caused by
 familial,
 tumors (craniopharyngioma),
 autoimmune,
 trauma
• The most common signs and symptoms of diabetes insipidus are:
 Extreme thirst
 Excretion of an excessive amount of diluted urine
 Depending on the severity of the condition, urine output
can be as much as 16 quarts (about 15 liters) a day if you're
drinking a lot of fluids. Normally, a healthy adult will
urinate an average of less than 3 quarts (about 3 liters) a
day.
 Other signs may include needing to get up at night to
urinate (nocturia) and bed-wetting.

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 Oxytocin
1. Stimulates contraction of smooth muscle in
the uterus (the sensitivity of the uterus to
oxytocin increases in late pregnancy
causing uterine contractions and essential
for the birth process).
2. Smooth muscle contractions in the
mammary glands result in milk ejection.
3. Promotes maternal behavior toward the
newborn.

• Oxytocin release is stimulated by:

1. mechanical stimulation of the breast nipple,
such as occurs in suckling, or of the vagina and
uterus;
2. emotional correlates of human reactions to
sexual excitement or the crying of a baby.

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 The Adrenal Glands

1) Adrenal cortex – steroid hormones

2) Adrenal medulla – catecholamines
40
 Hormones of the Adrenal Cortex

• All the hormones of adrenal cortex are derivates of cholesterol.

• ACTH controls the release of both cortisol and adrenal androgens.
• Aldosterone is stimulated by a rise in angiotensin II and/or K+. 41
 Physiological Effects of Glucocorticoids
Main glucocorticoid secreted by adrenal cortex is cortisol. Corticosterone is not
important under normal conditions.
1. Stress
Stress includes states such as trauma, exposure to cold, illness, starvation, and
exercise.
The capacity to withstand stress is dependent on adequate secretion of the
glucocorticoids.
Stress hormones usually act to mobilize energy stores. The stress hormones are:
• Growth hormone: mobilizes fatty acids by increasing lipolysis in adipose tissue
• Glucagon: mobilizes glucose by increasing liver glycogenolysis
• Cortisol: mobilizes fat, protein, carbohydrate
• Epinephrine, in some forms of stress such as exercise: mobilizes glucose via
glycogenolysis and fat via lipolysis
All stress hormones raise plasma glucose.
Severe hypoglycemia is a crisis and causes a rapid increase in all stress hormones.
By definition, because these hormones raise plasma glucose, they are refferred to as
counterregulatory hormones (opposite to insulin).
A deficiency in a stress hormone may cause hypoglycemia.
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 Physiological Effects of Glucocorticoids
2. Metabolic effects
Cortisol promotes the mobilization of energy stores, specifically:
• Proteins: Cortisol promotes degradation and increased delivery of hepatic gluconeogenic
precursors.
• Lipids: Cortisol promotes lipolysis and increased delivery of free fatty acids and glycerol.
• Carbohydrates: Cortisol raises blood glucose, making more glucose available for nervous
tissue by two mechanisms:
- Cortisol counteracts insulin's action in most tissues (muscle, lymphoid, and fat).
- Cortisol increases hepatic output of glucose via gluconeogenesis from amino acids in
particular (not from liver glycogenolysis).
3. Immune suppression: decrease amount and activity of leucocytes especially lymphocytes,
inhibit production of immunoglobulin (antibodies);
4. Anti-inflammatory effect: inhibits production of macrophages, granulocytes and
hyaluronic acid and collagen, decrease permeability of endothelium thus preventing swelling
and inflammation development;
5. Anti-allergic effect: inhibit degranulation of mast cells, macrophages, and granulocytes:
mast cells are the source of histamine, while macrophages and granulocytes release
serotonin and lysosomal enzymes. Cortisol stabilizes membranes and, thereby, inhibits the
release of these factors in allergies or during inflammation
6. Increase blood pressure:
 increase sensitivity of the receptors of smooth muscles of vessels to vasoconstrictors
(catecholamine, angiotensin II),
 inhibit vasodilator effect of nitric oxide, increase synthesis of angiotensinogen;
7. Water-ion balance – increase water and sodium retention
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Control of ACTH and cortisol secretion
CRH control
• Secretion of CRH increases in
response to stress and in
the early morning:
• Peak cortisol secretion
occurs early in the morning
between the 6th and 8th
hours of sleep.
• Secretion then declines
slowly during the day and
reaches a low point late in
the evening.
ACTH control
• Stimulates the secretion of
cortisol (and adrenal
androgens) of adrenal
cortex.
• Cortisol suppresses the
release of ACTH by acting on
the hypothalamus and an-
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terior pituitary.
 Adrenal cortex dysfunction
Adrenal Insufficiency Cushing disease (high ACTH)
(Primary - Addison's Disease) Cushing syndrome (excess amounts of cortisol)

• Primary adrenal insufficiency (disorder of the • Symptoms:

adrenal glands themselves + high level of • Weight gain and fatty tissue deposits,
ACTH) or secondary adrenal insufficiency particularly around the midsection and
(inadequate secretion of ACTH by the pituitary upper back, in the face (moon face),
and between the shoulders (buffalo
gland). hump)
• The symptoms of Addison's Disease: • Pink or purple stretch marks (striae) on
• Chronic fatigue and muscle weakness, the skin of the abdomen, thighs,
breasts and arms
• loss of appetite,
• Thinning, fragile skin that bruises easily
• weight loss • facial hair (hirsutism) in women
• Nausea, vomiting, and diarrhea • Irregular or absent menstrual periods
• Low Blood pressure • Decreased libido, decreased fertility,
• areas of skin hyperpigmentation, or dark erectile dysfunction in men
tanning (darkening is most visible on scars, • Severe fatigue, muscle weakness,
elbows, knees and toes, lips, and mucous depression, anxiety and irritability
membranes) caused by effect of excess ACTH • high blood pressure, headache
on the melanocytes to produce melanin that
bind to the melanocortin 1 receptor on the
surface of dermal melanocytes).
• Hypoglycemia,
• menstrual periods may become irregular or 45
stop.
 Adrenal disorders
Cushing syndrome

• is excess cortisol secretion owing to any of several

causes:
 ACTH hypersecretion by the pituitary,
 ACTH-secreting tumors,
 hyperactivity of the adrenal cortex independently
of ACTH
• Cushing syndrome disrupts carbohydrate and protein
metabolism, leading to hyperglycemia, hypertension,
muscular weakness, and edema
• Some patients exhibit abnormal fat deposition
between the shoulders (“buffalo hump”) or in the
face (“moon face”)
• Long-term hydrocortisone therapy can have similar
effects.

46
 Hormones of Adrenal Medulla
• Secretion of the adrenal medulla is 20% norepinephrine and 80%
epinephrine.
• Phenylethanolamine-N-methyltransferase (PMNT) converts norepinephrine
into epinephrine.
• Half-life of the catecholamines is only about 2 minutes. Metabolic end-
products include metanephrines and vanillylmandelic acid (VMA) both of
which can be measured in plasma and urine
• Removal of the adrenal medulla reduces plasma epinephrine to very low
levels but does not alter plasma norepinephrine. Most circulating nor-
epinephrine arises from postganglionic sympathetic neurons.
• Because many of the actions of epinephrine are also mediated by nor-
epinephrine, the adrenal medulla is not essential for life.
• The vasoconstrictive action of norepinephrine is essential for the main-
tenance of normal blood pressure, especially when an individual is standing.
Plasma norepinephrine levels double when one goes from a lying to a
standing position. People with inadequate production of norepinephrine
suffer from orthostatic hypotension.
• Epinephrine is a stress hormone and rapidly increases in response to
exercise, exposure to cold, emergencies, and hypoglycemia. 47
 THE ADRENAL MEDULLA
• The adrenal medulla contains neuronal cells (chromaffin cells) synthesizing
the catecholamines.
• The preganglionic autonomic supply of the adrenal medulla is chiefly by way
of the greater splanchnic nerve.
• The significant catecholamines are dopamine, epinephrine, and
norepinephrine.
• The adrenal medulla is stimulated under conditions of stress, and leads to
many effects:
1. metabolic effects ensure an increased supply of glucose and free fatty acids;
2. cardiovascular effects ensure both increased cardiac output and preferential
distribution of cardiac output to brain, heart, and skeletal muscle.
Adrenoreceptors: Epinephrine has higher affinity for β-adrenoreceptors, whereas
norepinephrine has greater affinity for α-adrenoreceptors.
3. Actions of Dopamine - it dilates the renal afferent and mesenteric arterioles
but constricts all other vascular beds, increases cardiac performance, probably
by activating β1-adrenoreceptors.
Dopaminergic receptors. There are five subtypes of dopaminergic receptors (D1 to
D5), and they are located mainly and in different parts of the brain.
• All are G protein–coupled receptors.
• Activation of D1 and D5 increases cytosolic cAMP,
• Activation of D2, D3, and D4 decreases cytosolic cAMP. 48
Metabolic Action of Catecholamines
• Liver: Epinephrine increases the
activity of liver and muscle
phosphorylase, promoting
glycogenolysis. This increases
glucose output by the liver.
• Skeletal muscle: Epinephrine
promotes glycogenolysis but
because muscle lacks glucose-6-
phosphatase, glucose cannot be
released by skeletal muscle;
instead, it must be metabolized at
least to lactate before being
released into the circulation.
• Adipose tissue: Epinephrine
increases lipolysis in adipose
tissue by increasing the activity of
hormone-sensitive lipase.
Glycerol from TG breakdown is a
minor substrate for
gluconeogenesis.
• Epinephrine increases the
metabolic rate. This will not occur
without thyroid hormones or the
adrenal cortex.
49
 Adrenal disorders
• Pheochromocytoma is a tumor of the adrenal medulla
• Malignant cells secrete excessive amounts of epinephrine
and norepinephrine
• Symptoms:
 hypertension,
 elevated metabolic rate,
 nervousness,
 indigestion,
 hyperglycemia
 glycosuria
 headache
 palpitation
 anxiety

50
 Growth Hormone
• pulsatile manner of secretion - every 4
hours, peaking within 2 hours of falling
asleep;
• GH secretion is controlled by growth
hormone–releasing hormone (GH-RH)
and somatostatin (SS), both synthesized
in the hypothalamus
• Growth hormone secretion is feedback
inhibited by GH itself and by insulin-like
growth factor-1 (IGF-1), or by an
abundance of plasma glucose or free fatty
acids.
• Growth hormone secretion is stimulated
by three classes of physiologic challenges:
1) decreased availability of energy
substrates for cells (for example,
fasting);
2) increased plasma levels of certain
amino acids;
3) stress.
51
 Effects of GH

1. Biologic effects of GH • somatomedins are produced

vary widely and include: in the liver, cartilage, and
other tissues in response to
 actions on stimulation by GH and a
electrolytes, variety of other factors,
including insulin.
 energy metabolism, • Glucocorticoids, estrogen,
 stimulation of depress somatomedin
somatomedins activity.
synthesis • In humans, the principal
somatomedin is IGF-1 (also
called somatomedin C)

52
 GH actions dependent on
somatomedins
Growth Increase cell size
Increase rate of cell division
Increase longitudinal growth of
cartilage and bone
Increase bone circumference
Metabolism Increase protein synthesis
Increase body mass

53
 Dysfunction of GH
hyposecretion of GH hypersecretion of GH
• in infants and children leads to • Chronic hypersecretion of GH
dwarfism; before the ossification causes
• Symptoms: prolonged growth in long bones,
• the stature is short because of resulting in giantism.
delayed bone growth. • In adults chronically elevated GH
• mild obesity and retard levels result in acromegaly.
development of adult reproductive • Symptoms: an increased diameter
functions of fingers, toes, hands, and feet; the
• In contrast to the dwarfism caused deposition of heavy bony ridges
by hyposecretion of thyroid above the eyes; and a prominent
hormones, theses dwarfs exhibit jaw, a bulbous and broad nose, and
normal intelligence. enlarged tongue, thickened skin,
and sparse subcutaneous adipose
• No obvious pathology is associated tissue.
with hyposecretion of GH in adults,
it can lead to reduced bone mineral • Chronic hyperglycemia results,
content in adults. frequently leading to diabetes
mellitus. 54
55
ACROMEGALIA

56
 Hypothalamo-pituitary-thyroid axis
Thyroid-Stimulating Hormone
• Secretion is pulsatile, with peaks
occurring every 2 to 4 hours;
• lowest in the morning,
• rises from about 21:00 onward,
• and reaches a peak near midnight.
• The secretion rate is increased by TRH
and decreased by somatostatin as well
as by negative feedback by the thyroid
hormones T3 and T4.
• The TSH is the major regulator of
thyroid function and thyroid size.
• It rapidly stimulates the thyroid to
increase iodide trapping and binding to
synthesize T3 and T4.

57
 The Thyroid Gland
• The thyroid gland is the largest
endocrine gland; it weighs 20 to 25 g
and receives one of the body’s
highest rates of blood flow per gram
of tissue.
• It consists of two large lobes, one on
each side of the trachea,
• Histologically, the thyroid is
composed mostly of sacs called
thyroid follicles. Each is filled with a
protein-rich colloid and lined by a
simple cuboidal epithelium of
follicular cells. These cells secrete
two main thyroid hormones:
• T3 (triiodothyronine), and
• T4 (thyroxine), also known as
tetraiodothyronine. 58
 Biological effects of thyroid hormones
1. Effects of thyroid hormones on development and
growth:
• In fetal life and the early postnatal period, thyroid
hormones promote body growth and normal
development of nervous tissue including
1) promotion of dendrite branching,
2) proliferation of axons,
3) formation of synapses, and
4) myelinization and growth of glia, cerebellar
cortex, and cerebral cortex.
• Absence of thyroid hormones causes cretinism -
growth disturbances and severe mental
retardation.

• From birth onward, thyroid hormones stimulate

development, linear growth, and maturation of
bone, as well as chondrocyte activity:
1) growth hormone secretion and somatomedin
synthesis,
2) somatomedin action at the epiphyseal growth
plate in bone.
59
Biological effects of thyroid hormones (continuation)
2. Effects of thyroid hormones on energy metabolism:
• In adults, the main physiologic role of thyroid hormones is the
regulation of energy metabolism:
1) increase metabolic rate,
2) O2 consumption,
3) heat production,
4) stimulation of Na+-K+-pump synthesis - calorigenic effect
• Thyroid hormones and carbohydrate metabolism:
1) intestinal carbohydrate absorption and whole-body glucose
turnover,
2) glucose utilization (particularly in muscle and adipose tissue),
3) hepatic glycogenolysis.
• Thyroid hormones and fat metabolism:
1) stimulate cholesterol synthesis,
2) its conversion to bile and bile secretion,
3) formation of low-density lipoprotein (LDL) receptors in the liver
60
 Biological effects of thyroid hormones (continuation)
3. Cardiovascular and respiratory effects of thyroid hormones:
1) increase the number and affinity of cardiac β-adrenoreceptors;
2) increase expression of sarcolemmal Ca++-ATPase;
3) decrease the barrier function of capillary endothelial cells and, thereby,
promote extravasation of albumin and edema formation
The cardiovascular effects are increased cardiac output and decreased total
peripheral resistance (arising from both enhanced β-adrenergic activity and
cutaneous vasodilatation, which is a reflex response to increased heat
production and body temperature).

4. Endocrine effects of thyroid hormones:

• Thyroid hormones affect a variety of hormone systems:
1) potentiate the actions of insulin in the promotion of glyconeogenesis
and glucose utilization;
2) alter menstrual patterns in that lack of thyroid hormone is associated
with excessive and frequent menstrual bleeding, whereas excess thyroid
hormone causes reduction or cessation of menstrual bleeding;
3) alter sensitivity to catecholamines by increasing the number and affinity
of β-adrenergic receptors.
61
 Dysfunction of thyroid gland
Hypothyroidism Hyperthyroidism
• In children and teens (cretinism) • Sudden weight loss, even when your appetite
 Poor growth, resulting in short stature and the amount and type of food you eat
 Delayed development of permanent teeth remain the same or even increase
 Delayed puberty • Tachycardia — commonly more than 100
 Poor mental development beats a minute — irregular heartbeat
• In adults (mixedema) (arrhythmia) or pounding of your heart
• Fatigue (palpitations)
• Increased sensitivity to cold • Increased appetite
• Constipation • Nervousness, anxiety and irritability
• Dry skin • Tremor — usually a fine trembling in your
• Weight gain hands and fingers
• Puffy face • Sweating
• Muscle weakness • Changes in menstrual patterns
• Heavier than normal or irregular menstrual • Increased sensitivity to heat
periods • Changes in bowel patterns, especially more
• Thinning hair frequent bowel movements
• Slowed heart rate • An enlarged thyroid gland (goiter), which may
• Depression appear as a swelling at the base of the neck
• Impaired memory • Difficulty sleeping
• Skin thinning 62
 Diseases of thyroid and parathyroid glands

• Severe or prolonged adult • Goiter (toxic, and endemic)

hypothyroidism can course – hypersecretion of TH
Myxedema – hyposecretion of TH

63
 Hypothalamo-pituitary-gonadal axis
Gonadotropins
FSH and LH regulate ovarian and testicular function
• Gonadotropin secretion is promoted by Gn-RH and
inhibited by negative feedback from the gonadal steroids,
estrogens, progesterones, and androgens
• Also Gn-RH is present in various regions of the limbic
system and is involved in modulating emotional aspects
of sexual behavior.
• Follicle-stimulating hormone.
• In women - growth of ovarian follicles in preparation for
the next ovulation cycle and stimulates follicle to
synthesize estradiol.
• In men - stimulates secretory activity in Sertoli’s cells and
helps maintain the spermatogenic epithelium.
• Luteinizing hormone.
• In women - stimulates the ovarian cells to produce
androgens, which then diffuse to the granulosa cells,
where they are converted to estrogens.
• initial formation of the corpus luteum and secretion of
progesterone;
• In men - primarily responsible for controlling
testosterone synthesis in the Leydig cells of the testes. 64
 Prolactin
• Secretion is inhibited by prolactin-inhibiting factors,
mostly dopamine.
• Prolactin release is increased mainly by breast suckling
and also by mechanical stimulation of the cervix
(prolactin-releasing factors, thyroid-releasing hormone,
serotonin, and vasoactive intestinal peptide (VIP) may
act as releasing factors)
• Actions of prolactin.
• It promotes growth of mammary gland and milk
secretion: by increasing the local production of casein
and lactalbumin.
• It increases lipoprotein lipase activity in the mammary
gland, and this promotes high fat content in human milk.
• It inhibits Gn-RH secretion and its effects resulting in
inhibition of ovulation while a woman is breast-feeding
causing lactation amenorrhea.
• The actions of prolactin in men are uncertain, however,
excess prolactin causes hypogonadism and impotence.
65
Target endocrine glands and their hormones

Thymus • The thymus is located in the

mediastinum superior to the
heart
• It is large in infants and
children but involutes after
puberty
• In elderly people, it is a
shriveled vestige of its
former self, with most of its
parenchyma replaced by
fibrous and adipose tissue.
• The thymus secretes
thymopoietin and
thymosins, hormones that
regulate the development
and later activation of
T-lymphocytes.

66
 Regulation of calcium homeostasis
CALCITONIN
• Synthesis and Secretion:
• C cells (parafollicular cells) of thyroid;
• stimulated primarily by elevated levels of plasma
[Ca++], also by estrogens, dopamine,β-adrenergic
agonists, gastrin, cholecystokinin, glucagon, and
secretin;
• inhibited by low plasma [Ca++].
• Actions of Calcitonin
• Lowering of extracellular [Ca++] by inhibiting bone
resorption and promoting urinary Ca++ excretion.
• Its long-term effects on serum Ca++ are small in
adult humans because such effects trigger
compensatory changes in osteoblastic activity and
parathyroid hormone secretion. 67
The Parathyroid Glands
• The parathyroid glands are partially
embedded in the posterior surface of
the thyroid
• There are usually four, each about 3
to 8 mm long and 2 to 5 mm wide
• Major physiological role of PTH is
homeostasis of calcium and
phosphate
• PTH is secreted in response to
hypocalcemia
• Biological effects:
 promotes intestinal calcium
absorption;
 inhibits urinary calcium excretion;
 promots phosphate excretion (so
the phosphate does not combine
with calcium and deposit into the
bones); and
 stimulates osteoclasts to resorb
bones. 68
69
 Natriuretic peptides are hormones which are mainly
secreted from heart and have important natriuretic and
kaliuretic properties

• Atrial natriuretic peptide (ANP) is synthesized, stored, and

released by atrial myocytes in response to atrial
distension, angiotensin II stimulation, endothelin,
and sympathetic stimulation (beta-adrenoceptor mediated),
during hypervolemic states (elevated blood volume), such as
occurs in heart failure.
• Brain-type natriuretic peptide (BNP) is synthesized largely by
the ventricles (as well as in the brain where it was first
identified).
• Neutral endopeptidase (NEP; also called neprilysin) is a
circulating enzyme that degrades natriuretic peptides.
Therefore, inhibition of this enzyme increases circulating levels
of natriuretic peptide and potentiates their effects.

70
 Effects of ANP and BNP
ANP, BNP are released by the same mechanisms
and they have similar physiological actions

71
 ENDOCRINE PANCREAS
• The endocrine pancreas comprises only 1 to 2% of the organ
and consists of highly vascularized islands, called the islets of
Langerhans.
• Islets of Langerhans distributed throughout the pancreas and
contain four distinct cell types, each being responsible for the
synthesis, storage, and release of one of the hormones:
• insulin (β cells),
• glucagon (α cells),
• somatostatin (δ cells),
• pancreatic polypeptide (F cells).
• Each islet consists mostly of β cells (up to 80% of the islet).
• Each cell secretes its endocrine product into capillaries by
exocytosis.
• Islets are innervated by sympathetic adrenergic,
parasympathetic cholinergic (right vagus) and contain
adrenergic (mainly α2) and muscarinic receptors (mainly M4).

72
 Insulin
• Insulin is secreted only by pancreatic β cells;
• Exocytosis of insulin-containing vesicles is initiated and maintained by elevation of
cytosolic [Ca++] in β cells above the normal resting value of 60 to 100 nmol/L which is
initiated by transmitter release in nerve terminals;
• The most important regulator is glucose, there is a measurable increase in insulin
secretion when plasma glucose concentration rises above its normal level of 100
mg/dL (5 mmol/L);
• Mechanism of insulin release
• Glucose enters pancreatic islet β cells via the GLUT-2 transporter, which does not
require insulin for activation;
• Intracellular metabolism of glucose produces ATP, which inhibits K+ channel and
restricts K+ outflow
• Causing depolarization of the cell, and causes voltage- gated Ca++ channels to
open raising intracellular Ca and lead to exocytosis of insulin-containing vesicles.
• increased intracellular [Ca++] will promote insulin secretion and decreased
intracellular [Ca++] will inhibit insulin secretion.
• If plasma glucose continues to be high, the process repeats.

73
Regulation of insulin secretion

74