By MD, PhD, Associate ProfessorBy MD, PhD, Associate Professor
Ivano-Frankivsk National MedicalIvano-Frankivsk National Me...
CONTENTCONTENT
1.1. Endocrine regulatory dysfunction.Endocrine regulatory dysfunction.
2.2. The main types of endocrine dy...
Actuality of the lecture.Actuality of the lecture.
 The endocrine system is involved in all of the integrative aspects of...
Role of endocrine system inRole of endocrine system in vitalvital
activity of theactivity of the organismorganism
• The en...
Chemical signalsChemical signals
 Chemicals found in both systems and also asChemicals found in both systems and also as
...
HormonesHormones can be synthesized:can be synthesized:
• а) by epithelial cells (one’s own
glandular ephithelium);
• b) b...
According to chemical nature theyAccording to chemical nature they
differentiatedifferentiate::
 аа)) steroid hormonesste...
Lipid-solubleLipid-soluble hormones (steroidhormones (steroid
hormones)hormones) pass easilypass easily throughthrough
cel...
According to functional effectsAccording to functional effects
hormones can be:hormones can be:
 а) affectors (act direct...
Multiple Effects of HormonesMultiple Effects of Hormones
 The same hormone may have differentThe same hormone may have di...
Glycogen
deposits
β receptor
Vessel
dilates.
Epinephrine
(a) Liver cell
Epinephrine
β receptor
Glycogen
breaks down
and gl...
Mechanisms of hormone actionMechanisms of hormone action
1. Target cells [with receptors]1. Target cells [with receptors]
...
Target cell specificityTarget cell specificity
1. Blood levels of hormone1. Blood levels of hormone
2. Number of hormone r...
Etiology of endocrine disordersEtiology of endocrine disorders
 Reasons and kinds of endocrine disorders.Reasons and kind...
There are three variants ofThere are three variants of
endocrine functions disorders:endocrine functions disorders:
1. Hyp...
Pathogenesis of endocrinePathogenesis of endocrine
disordersdisorders
• The mechanisms of function
disorders of an endocri...
DisordersDisorders of endocrine gland regulationof endocrine gland regulation
 RegulationRegulation ofof endocrine glande...
 Pathological processes which are
primarity developed in hypothalamusprimarity developed in hypothalamus lead
to disorder...
 TranshypophysarTranshypophysar regulation includesregulation includes synthesis ofsynthesis of
peptidespeptides which ar...
• By means of parahypophysarparahypophysar mechanism
secretory, vessel and trophic influence of CNS on
the function of end...
 The disorders ofThe disorders of trans- andtrans- and
parahypophysarparahypophysar regulationregulation
leads to disfunc...
Role of mechanisms feedback bondRole of mechanisms feedback bond
in endocrine disturbancesin endocrine disturbances
• TheT...
Pathway Example
Stimulus
Low pH in
duodenum
S cells of duodenum
secrete secretin ( )
Endocrine
cell
Blood
vessel
PancreasT...
Control of hormone releaseControl of hormone release
1. Negative feedback ["stimulatory-inhibitory"]
2. Positive feedback ...
Disorders of hormones biosynthesisDisorders of hormones biosynthesis
and their secretionand their secretion
• Strictly gla...
The main possible reasons of protein-The main possible reasons of protein-
peptide hormones synthesis disorders are:peptid...
Disorders of transport, reception and
hormones metabolism
• The peripheral mechanisms determine activity of hormones
excre...
DisorderDisorderss ofof endocrineendocrine functions, connectedfunctions, connected
with disturbanceswith disturbances of ...
This gland makes me wake up in theThis gland makes me wake up in the
morning and ready to go!morning and ready to go!
Pine...
Coordination of Endocrine andCoordination of Endocrine and
Nervous Systems in VertebratesNervous Systems in Vertebrates
Th...
This glandThis gland
is called theis called the
“master gland”“master gland”
because itbecause it
secretes ninesecretes ni...
Tropic effects only:
FSH
LH
TSH
ACTH
Nontropic effects only:
Prolactin
MSH
Nontropic and tropic effects:
GH
Anterior
Pituitary
Posterior
pituitary Stimulates milk
ejection and uterine
contractions
Ovary and testisOxytocin
Conserva...
Type ofType of
AdenomaAdenoma
SecretionSecretion StainingStaining PathologyPathology
CorticotrophicCorticotrophic
adenomas...
Disturbances of functions of hypophysis.
Hypofunction of adenohypophysis
(hypopituitaritism)
There are panhypopituitarity ...
Panhypopituitarity – is the decrease ofPanhypopituitarity – is the decrease of
formation of all adenohypophysis hormonesfo...
Hypophyseal
Simond’s
cachexia
Causes of HypopituitarismCauses of Hypopituitarism
Tumors and mass lesions — pituitary adenomas, cysts,
metastatic cancer,...
Partial hypopituitarityPartial hypopituitarity
is the disorder of
formation of separate
hormones
of adenohypophysis
(not a...
• The insufficiency of STHThe insufficiency of STH results to
development of hypophysar dwarfishness,
or nanism and appear...
By producing too much of one or more hormonesBy producing too much of one or more hormones
• Adrenocorticotropic hormoneAd...
 Insufficiency of TTHInsufficiency of TTH
causes secondarycauses secondary
decrease function ofdecrease function of
thyro...
 Insufficiency of gonadotropic hormonesInsufficiency of gonadotropic hormones
results inresults in decrease of ability of...
Hyperfunction ofHyperfunction of
adenohypophysisadenohypophysis
(hyperpituitarism)(hyperpituitarism)
 The main reasons of...
GigantismGigantism
Jane Bunford 2.41mJane Bunford 2.41m
Zeng Jinlian 249 smZeng Jinlian 249 smYao Defen 2.34Yao Defen 2.34
• By producing too much of one or more
hormones
• Growth hormone: causes
ACROMEGALY
– a syndrome that includes:
• excessiv...
BITEMPORAL
HEMIANOPSIA
Usually the bitemporal hemianopsia isUsually the bitemporal hemianopsia is
NOT perfectly symmeetrical. Why?NOT perfectly s...
• 2. Basophilic adenomaBasophilic adenoma, grows
from basophilic cells of
adenohypophysis which more often
produce ACTH. D...
Hyperfunction of neurohypophysisHyperfunction of neurohypophysis
• Leads to redundant production vasopressin andLeads to r...
• OxytocinOxytocin renders the following functional
influences:
1) Stimulates secretion of milk (lactation) causing
contra...
GG
AA
LL
AA
CC
TT
OO
RR
RR
HH
EE
AA
Hypofunction ofHypofunction of
neurohypophysisneurohypophysis
 Insufficient production of vasopressin results toInsuffici...
Adrenal cortex
- secretes several classes of steroid hormones (glucocorticoids and
mineralocorticoids)
- with three concen...
Effects of
mineralocorticoids:
Effects of
glucocorticoids:
1. Retention of sodium
ions and water by
kidneys
2. Increased b...
Actions of CortisolActions of Cortisol
Major InfluenceMajor Influence Effect on BodyEffect on Body
Glucose metabolismGluco...
Disorders of adrenal gland functionDisorders of adrenal gland function
 The most frequently there are followingThe most f...
Insufficiency of adrenal cortex
• According to etiology there are primary and secondary
kinds of adrenal cortex insufficie...
• TheThe chronic insufficiencychronic insufficiency ofof
adrenals cortex is characterized foradrenals cortex is characteri...
Skin hyperpigmentation at case of Adison’s disease
ІІ. Manifestation, connected with the falling of. Manifestation, connected with the falling of
mineralocorticoids function...
ІІІІ. Manifestations stipulated by disorders of. Manifestations stipulated by disorders of
glucocorticoid function of adre...
Increase of adrenals cortex functionIncrease of adrenals cortex function
• HyperaldosteronismHyperaldosteronism.. Arises d...
• There are two clinical forms of
hypercorticism with
hyperproduction of
glucocorticoides:
1. Cushing’s diseaseCushing’s d...
MOON
FACIES
BUFFALO
HUMP
STRIAE
GlucocorticoidGlucocorticoid
hypercorticism appears by:hypercorticism appears by:
1) arterial hypertension;
2) hyperglycae...
• Adrenogenital syndromeAdrenogenital syndrome results from the
hereditary stipulated blockade of cortisole
synthesis and ...
Disorders of adrenal medulla functionDisorders of adrenal medulla function
 Hypofunction of adrenal medullaHypofunction o...
HYPOADRENALISMHYPOADRENALISM
Caused by any anatomic or metabolic lesion of the adrenalCaused by any anatomic or metabolic ...
ADRENAL MEDULLAADRENAL MEDULLA
PHEOCHROMOCYTOMA:PHEOCHROMOCYTOMA:
- associated with catecholamine-
Induced hypertension.
-...
 This large adrenal neoplasmThis large adrenal neoplasm
has been sectioned in half.has been sectioned in half.
Note the g...
 Cardiovascular:Cardiovascular: Coronary arteryCoronary artery
disease, hypertension, stroke, arrhythmia.disease, hyperte...
Literature:Literature:
1.1. General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin –General and clinical p...
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.
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Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.

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prepared by MD, PhD, Associate Professor, Marta R. Gerasymchuk,
pathophysiology department.
Ivano-Frankivsk National Medical University

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  • Major human endocrine glands
  • Receptor location varies with hormone type
  • One hormone, different effects
  • A simple endocrine pathway
  • Disorder of endocrine functions, connected with disturbances of hormones metabolism
    The destruction of protein-peptide hormones is realized in liver with the help of peptidase enzymes.
    The disturbances of metabolic hormones transformations can stimulate development of peripheral disorders of endocrine function. So, in case of slowing-down of hormones inactivation their contents in blood is increased, that appears in glands hyperfunction. And on the contrary, the accelerated transformation of hormones in their inactive forms is accompanied by development of endocrine hypofunction.
    In hepatitis and cyroses of a liver hormones metabolism is oppressed.
  • There are two types of cytoreception of hormones
    1. Membrane type of cytoreception. It is the main mechanism of action of protein- peptide hormones and catecholamines. Nowadays we known secondary intermediaties which are represented by the following substances:
    a) cyclic nucleotides - cAMP, cGМP;    
    b) ions of Са++;
    c) phospholipide messangers- diacilglycerol (DAG) and inozitoltriphosphate (ITP).
    The specificity of the answer of a cell on this or other hormone is determined by specificity of the receptor, which is connected only with a certain hormone, and also by nature of specific to a cell proteinkinase and protein substrats.
    2. Intracellular  type of cytoreception. It is in the base of  mechanism of steroid and thyroid hormones action.
    The blockade of hormonal receptor is the widespread mechanism, which results to hormonal insufficiency: active hormone does not find receptor on a cell or in it  because of receptor  loss or fixing on its surface of antagonist, conformation changes of the receptor, which interfere connection with the hormone. Usually concentration of hormone in such cases is normal or increased. The introduction of the hormones with the medical purpose is not accompanied by appropriate effect.
  • The pineal gland (also called the pineal body, epiphysis cerebri, epiphysis or the "third eye") is a small endocrine gland. It produces melatonin, a hormone that affects the modulation of wake/sleep patterns and photoperiodic (seasonal) functions. It is located near to the center of the brain between the two hemispheres, tucked in a groove where the two rounded thalamic bodies join. Unlike much of the rest of the brain, the pineal gland is not isolated from the body by the blood-brain barrier system. It is reddish-gray and about the size of a pea (8 mm in humans).
  • Anterior pituitary lobe = adenohypophysis = Rathke’s pouch = pars distalis. Hormones released here are also made here. Anterior lobe is WiFi.
    Posterior pituitary lobe = neurohypophysis = infundibulum = pars nervosa. Hormones released here are made in the hypothalamus. Posterior lobe is Hard-Wired.
  • Hormones from basophils go to other endocrine glands, thyroid, adrenal cortex, ovary, testis. Cells from acidophils do NOT.
    Acidophils make GROWTH related hormones.
    Basophils make hormones which stimulate other endocrine glands.
    Chromophobes make NOTHING.
    The posterior pituitary (aka, pars nervosa or neurohypophysis) looks like typical brain tissue. Why? Ans: It IS typical brain tissue. The pituicytes are glial cells. Herring bodies are massively dilated terminal axons from the hypothalamus.
    The posterior pituitary does not make these hormones, it just releases them. The hypothalamus actually makes the hormones and transfers it down the stalk to the neurohypophysis.
  • A tropic hormone regulates the function of endocrine cells or glands
    The four strictly tropic hormones are
    Thyroid-stimulating hormone (TSH)
    Follicle-stimulating hormone (FSH)
    Luteinizing hormone (LH)
    Adrenocorticotropic hormone (ACTH)
  • Anterior pituitary hormones:
    1. Pro-opiomelanocortin [POMC]: a prohormone which is the source of adrenocorticotropic hormone (ACTH), some enkephalins and endorphins and melanocyte-stimulating hormone (MSH)
    2. Growth hormone [GH] or somatotropin
    3. Thyroid-stimulating hormone [TSH] [a hormone that has as its primary function the regulation of hormone secretion by another endocrine gland is classified functionally as a "tropic" ("nourishing") hormone]
    a.Thyroid gland: metabolism, growth & development; secretes calcitonin
    4. Adrenocorticotropic hormone [ACTH] [“tropic”]
    a. The adrenal cortex, the outer layer of the adrenal gland, secretes aldosterone [Na+ & K+ balance], cortisol [glucose, protein & lipid metabolism; the "stress hormone"] & sex hormones [including dehydroepiandrosterone]
    5. Gonadotropins [“tropic”]
    a. Follicle-stimulating hormone [FSH] & Luteinizing hormone [LH] [also called Interstitial cell- stimulating hormone [ICSH] in males
    6. Prolactin
    The posterior pituitary & hypothalamic hormones
    Oxytocin [the drug pitocin induces labor]
    Satisfactional Hormone? [Active in both sexes; helps orchestrate many of life's more pleasurable social & sexual interactions. Affects relationships between males & females, parents & offspring, neighbor & neighbor. Major role in human sexuality & happiness (high levels in males moments before orgasm and during ejaculation (The New York Times 1-22-91)]
    2. Antidiuretic hormone [ADH] [vasopressin]
    “Rakish Rodents Reformed” Vasopressin modulates male social behavior in a wide variety of mammals. In pair-bonding prairie voles the brain receptor for vasopressin is abundant, while in promiscuous meadow voles, males have much less of the receptor. It’s a story of “Wow, this feels good, and I’m with her” vs. “This is a female, and I want to do this again” (Discover, 1/2005)]
  • What kind of cells of the pituitary might be proliferating here? (acidophil or basophil)
  • What part of the optic nerves/chiasm/tracts would have to be injured to produce this?
  • Usually the bitemporal hemianopsia is NOT perfectly symmeetrical. Why? Because pituitary tumors are under no law to grow perfectly midline.
  • Galactorrhea in a young woman (non pregnant of course) is often the expression of an acidophil tumor of the adenohypophysis.
    Hyperprolactinemia is the most common anterior pituitary disorder and has many causes. Pathologic hyperprolactinemia, caused by prolactin-secreting adenomas (prolactinomas) or other clinical states that result in elevated prolactin levels such as primary hypothyroidism or dopamine-receptor blocking drug therapy, must be distinguished from the physiologic hyperprolactinemia of pregnancy and lactation. Roughly 40% of tumors found in autopsies are prolactinomas. Most of the patients had no symptoms from microadenomas and died of unrelated causes.
     
  • 1. The Adrenal Cortex
    Corticosteroids [adrenocortical hormones]
    * Mineralocorticoids: regulation of extracellular electrolytes [e.g., Na+, K+]
    * Aldosterone
    * Glucocorticoids: energy metabolism and stress responses
    * Cortisol [raises blood glucose, promotes "glucose sparing", suppresses inflammation]
    * Gonadocorticoids [sex hormones]
    * Testosterone, estrogen
    2. Adrenal Medulla
    a. Sympathetic "ganglia" [ANS fight or flight]
    * Epinephrine [E] and norepinehrine [NE]
  • Figure 45.21b Stress and the adrenal gland
  • What kind of cells of the pituitary might be proliferating here? (acidophil or basophil)
  • Pathophysiology of the endocrine system. General adaptation syndrome. Violation of hypophysis and adrenal glands.

    1. 1. By MD, PhD, Associate ProfessorBy MD, PhD, Associate Professor Ivano-Frankivsk National MedicalIvano-Frankivsk National Medical UniversityUniversity Pathophysiology of the endocrinePathophysiology of the endocrine system. General adaptationsystem. General adaptation syndrome. Violation ofsyndrome. Violation of hypophysis and adrenal glands.hypophysis and adrenal glands.
    2. 2. CONTENTCONTENT 1.1. Endocrine regulatory dysfunction.Endocrine regulatory dysfunction. 2.2. The main types of endocrine dysfunctions: hyper-,The main types of endocrine dysfunctions: hyper-, hypo- and dysfunction. Gland disorders of endocrinehypo- and dysfunction. Gland disorders of endocrine function.function. 3.3. Peripheral disorders of endocrine function.Peripheral disorders of endocrine function. 4.4. Panhypopituitarism: causes, mechanisms ofPanhypopituitarism: causes, mechanisms of development, main manifestations.development, main manifestations. 5.5. Partial hypofunction of adenohypophysis.Partial hypofunction of adenohypophysis. 6.6. Hyperfunction of adenohypophysis: eosinophilic andHyperfunction of adenohypophysis: eosinophilic and basophilic adenoma. Cushing’s disease.basophilic adenoma. Cushing’s disease. 7.7. Disorders of hypothalamo-neurohypophysealDisorders of hypothalamo-neurohypophyseal system. Disorders of secretion of antidiureticsystem. Disorders of secretion of antidiuretic hormone.hormone. Diabetes insipidus.Diabetes insipidus. 8.8. Describe the etiology, pathogenesis, andDescribe the etiology, pathogenesis, and manifestations of hyperfunction and hypofunction ofmanifestations of hyperfunction and hypofunction of the adrenal cortex.the adrenal cortex. 9.9. Characterize aCharacterize adrenal medulla hyperfunction.drenal medulla hyperfunction. 10.10. Describe SelyeDescribe Selye′′s historic general adaptations historic general adaptation syndrome; cite its stages. How does stress reactionssyndrome; cite its stages. How does stress reactions develop?develop?
    3. 3. Actuality of the lecture.Actuality of the lecture.  The endocrine system is involved in all of the integrative aspects ofThe endocrine system is involved in all of the integrative aspects of life, including growth, sex differentiation, metabolism, andlife, including growth, sex differentiation, metabolism, and adaptation to an ever-changing environment. This chapter focusesadaptation to an ever-changing environment. This chapter focuses on general aspects of endocrine function, organization of theon general aspects of endocrine function, organization of the endocrine system, hormone receptors and hormone actions, andendocrine system, hormone receptors and hormone actions, and regulation of hormone levels.regulation of hormone levels.  The endocrine system uses chemical substances calledThe endocrine system uses chemical substances called hormoneshormones as a means of regulating and integrating body functions. Theas a means of regulating and integrating body functions. The endocrine system participates in the regulation of digestion, use,endocrine system participates in the regulation of digestion, use, and storage of nutrients; growth and development; electrolyte andand storage of nutrients; growth and development; electrolyte and water metabolism; and reproductive functions. Although thewater metabolism; and reproductive functions. Although the endocrine system once was thought to consist solely of discreteendocrine system once was thought to consist solely of discrete endocrine glands, it is now known that a number of other tissuesendocrine glands, it is now known that a number of other tissues release chemical messengers that modulate body processes.release chemical messengers that modulate body processes.  The functions of the endocrine system are closely linked with thoseThe functions of the endocrine system are closely linked with those of the nervous system and the immune system.of the nervous system and the immune system.
    4. 4. Role of endocrine system inRole of endocrine system in vitalvital activity of theactivity of the organismorganism • The endocrine system relates the most important regulatoryregulatory systemssystems. It carries out regulatory influence with the help of hormoneshormones practically on all functions of an organism – metabolism, growth, reproduction, mental activity, adaptation, functional activity of all organs. •The endocrine system, alongThe endocrine system, along with the nervous system, iswith the nervous system, is responsible forresponsible for coordinating ourcoordinating our responsesresponses.. •The endocrine system is aThe endocrine system is a slowerslower system and the nervoussystem and the nervous system is asystem is a fasterfaster response.response.
    5. 5. Chemical signalsChemical signals  Chemicals found in both systems and also asChemicals found in both systems and also as part of other signaling mechanisms bind topart of other signaling mechanisms bind to specific receptor proteins on or in target cells.specific receptor proteins on or in target cells.  HormonesHormones – produced by endocrine glands,– produced by endocrine glands, travel through the blood stream to target organstravel through the blood stream to target organs ex – insulin, estrogenex – insulin, estrogen  Local regulatorsLocal regulators (a) paracrine signals – act on neighboring cells, ex.(a) paracrine signals – act on neighboring cells, ex. – cytokines, interferon, prostaglandins– cytokines, interferon, prostaglandins (b) autocrine signals – act on secreting cells itself,(b) autocrine signals – act on secreting cells itself, ex – cytokinesex – cytokines
    6. 6. HormonesHormones can be synthesized:can be synthesized: • а) by epithelial cells (one’s own glandular ephithelium); • b) by neuroendocrine cells (hypothalamic cells); • c) by myoendocrine cells (muscular fibres of heart atriums). – Neurotransmitters – secreted by neurons at synapses ex- serotonin, nitric oxide (NO) – Neurohormones – secreted by neurosecretory cells, travel through the blood stream to target organs or synapses ex- epinephrine – Pheromones – released into the environment; between individuals ex – insects marking trails, mating, etc. (a) Endocrine signaling Response Blood vessel (b) Paracrine signaling Response Response Response Response (c) Autocrine signaling Neuron (d) Synaptic signaling (e) Neuroendocrine signaling Neurosecretory cell Blood vessel
    7. 7. According to chemical nature theyAccording to chemical nature they differentiatedifferentiate::  аа)) steroid hormonessteroid hormones ((mineralmineral – and– and glucocorticoidsglucocorticoids, female and male, female and male sexual hormones);sexual hormones);  bb)) derivativesderivatives of aminoacidsof aminoacids ((thyreoidthyreoid hormones,hormones, catecholaminescatecholamines,, melatoninemelatonine););  cc)) protein peptideprotein peptide hormoneshormones ((releasingreleasing-hormones,-hormones, vasopressinvasopressin,, oxytocinoxytocin, hormones, hormones ofof adenohypophysis,adenohypophysis, insuline, glucagone, parathyrin,insuline, glucagone, parathyrin, calcitonine).calcitonine). Somatostatin
    8. 8. Lipid-solubleLipid-soluble hormones (steroidhormones (steroid hormones)hormones) pass easilypass easily throughthrough cell membranes, whilecell membranes, while water-water- solublesoluble hormones (polypeptideshormones (polypeptides and amines)and amines) do notdo not The solubility of a hormoneThe solubility of a hormone correlates with the location ofcorrelates with the location of receptors inside or on thereceptors inside or on the surface of target cellssurface of target cells • Water-solubleWater-soluble hormones are secretedhormones are secreted byby exocytosisexocytosis, travel freely in the, travel freely in the bloodstreambloodstream, and bind to cell-surface, and bind to cell-surface receptorsreceptors • Lipid-solubleLipid-soluble hormones diffusehormones diffuse acrossacross cell membranescell membranes, travel in the, travel in the bloodstream bound to transportbloodstream bound to transport proteins, and diffuse through theproteins, and diffuse through the membrane of target cellsmembrane of target cells Signal receptor TARGET CELL Signal receptor Transport protein Water- soluble hormone Fat-soluble hormone Gene regulation Cytoplasmic response Gene regulation Cytoplasmic response OR Signal receptor Water- soluble hormone Fat-soluble hormone TARGET CELL NUCLEUS(a) (b) Transport protein Signal receptor (a) NUCLEUS (b)
    9. 9. According to functional effectsAccording to functional effects hormones can be:hormones can be:  а) affectors (act directly on organs - targets);  b) tropic (regulate synthesis of effecting hormones);  c) releasing-hormones (regulate synthesis and secretion of tropic hormones).
    10. 10. Multiple Effects of HormonesMultiple Effects of Hormones  The same hormone may have differentThe same hormone may have different effects on target cells that haveeffects on target cells that have • Different receptors for the hormoneDifferent receptors for the hormone • Different signal transduction pathwaysDifferent signal transduction pathways • Different proteins for carrying out the responseDifferent proteins for carrying out the response due to different transcription factors theydue to different transcription factors they activateactivate  A hormone can also have differentA hormone can also have different effects in different specieseffects in different species
    11. 11. Glycogen deposits β receptor Vessel dilates. Epinephrine (a) Liver cell Epinephrine β receptor Glycogen breaks down and glucose is released. (b) Skeletal muscle blood vessel Same receptors but different intracellular proteins (not shown) Epinephrine β receptor Different receptors Epinephrine α receptor Vessel constricts. (c) Intestinal blood vessel
    12. 12. Mechanisms of hormone actionMechanisms of hormone action 1. Target cells [with receptors]1. Target cells [with receptors]  a. On cell membranea. On cell membrane  b. Inside the cellb. Inside the cell 2. Effects on target cells2. Effects on target cells  a. Membrane permeability or potentiala. Membrane permeability or potential  b. Protein synthesisb. Protein synthesis  c. Enzymesc. Enzymes  d. Secretiond. Secretion  e. Mitosise. Mitosis 3. Plasma membrane receptors and second-messenger systems [all3. Plasma membrane receptors and second-messenger systems [all amino acid-based hormonesamino acid-based hormones (except thyroid hormone) &(except thyroid hormone) & eicosanoids]eicosanoids]  a. The cyclic AMP signaling mechanisma. The cyclic AMP signaling mechanism 4. Intracellular receptors and direct gene activation [steroid (& thyroid)4. Intracellular receptors and direct gene activation [steroid (& thyroid) hormones]hormones]
    13. 13. Target cell specificityTarget cell specificity 1. Blood levels of hormone1. Blood levels of hormone 2. Number of hormone receptors [receptors are constantly being synthesized and broken down;2. Number of hormone receptors [receptors are constantly being synthesized and broken down; generally, a target cell hasgenerally, a target cell has 2000-100,000 receptors for a particular hormone2000-100,000 receptors for a particular hormone]] • a.a. Down-regulationDown-regulation: decrease in number of receptors [i.e., hormone levels are high]: decrease in number of receptors [i.e., hormone levels are high] • b.b. Up-regulationUp-regulation: increase in number of receptors [i.e., hormone levels are low]: increase in number of receptors [i.e., hormone levels are low] 3. Affinity of hormone & receptor3. Affinity of hormone & receptor 4. Other hormones [see below, "Interaction of hormones at target cells"]4. Other hormones [see below, "Interaction of hormones at target cells"] • Half-life, onset, and duration ofHalf-life, onset, and duration of hormone activityhormone activity 1. The concentration of a hormone reflects its rate of release, and the rate of inactivation and1. The concentration of a hormone reflects its rate of release, and the rate of inactivation and removal from the body.removal from the body. 2. The half-life of a hormone is the duration of time a hormone remains in the blood, and is2. The half-life of a hormone is the duration of time a hormone remains in the blood, and is shortest for water-soluble hormones.shortest for water-soluble hormones. 3. Target organ response and duration of response vary widely among hormones.3. Target organ response and duration of response vary widely among hormones. • Interaction of hormones at target cellsInteraction of hormones at target cells 1.1. PermissivenessPermissiveness [one hormone must be present in adequate amounts for the full exertion of[one hormone must be present in adequate amounts for the full exertion of another hormone's effect; e.g., thyroid hormone increases the number of receptors foranother hormone's effect; e.g., thyroid hormone increases the number of receptors for epinephrine in cells]epinephrine in cells] 2.2. SynergismSynergism [actions of several hormones are complementary and their combined effects is[actions of several hormones are complementary and their combined effects is grater than the sum of their separate effects; e.g., follicle stimulating hormone (FSH) andgrater than the sum of their separate effects; e.g., follicle stimulating hormone (FSH) and testosterone on spermatogenesis]testosterone on spermatogenesis] 3.3. AntagonismAntagonism [when one hormone causes the loss of another hormone's receptors; e.g.,[when one hormone causes the loss of another hormone's receptors; e.g., progesterone inhibits uterine responsiveness to estrogen]progesterone inhibits uterine responsiveness to estrogen]
    14. 14. Etiology of endocrine disordersEtiology of endocrine disorders  Reasons and kinds of endocrine disorders.Reasons and kinds of endocrine disorders. Among numerousAmong numerous ethiological factors of endocrine disorderss it is possible to selectethiological factors of endocrine disorderss it is possible to select the following main ones:the following main ones:  a mental trauma,a mental trauma,  necrosis,necrosis,  tumour,tumour,  inflamatory process,inflamatory process,  bacterial and viral infections,bacterial and viral infections,  intoxications,intoxications,  local disorders of blood circulation (hemorrhage, thrombosis),local disorders of blood circulation (hemorrhage, thrombosis),  alimentary disorders (deficiency of iodine and cobalt in food andalimentary disorders (deficiency of iodine and cobalt in food and drinking water, redundant consumption of carbohydrates),drinking water, redundant consumption of carbohydrates),  ionising radiation,ionising radiation,  inherent chromosome and gene defects.inherent chromosome and gene defects.
    15. 15. There are three variants ofThere are three variants of endocrine functions disorders:endocrine functions disorders: 1. HyperfunctionHyperfunction of endocrine glands 2. HypofunctionHypofunction of endocrine glands 3. DisfunctionDisfunction of endocrine glands Disfunction is characterized by different changes of hormonal production and production physiologic active precursors of their biosynthesis in the same endocrine gland or synthesis and entering in blood of atypical hormonal products.
    16. 16. Pathogenesis of endocrinePathogenesis of endocrine disordersdisorders • The mechanisms of function disorders of an endocrine gland can be various depending on localization and character of process. In pathogenesis of endocrine disorders it is possible to select three main mechanismsmechanisms: 1) Disorders of regulation of endocrine glands – disregulatory disorders; 2) Disorders of biosynthesis of hormones and their secretion – glandular disorders; 3) Disorders of the transport, reception and metabolism of hormones – peripheral disorders.
    17. 17. DisordersDisorders of endocrine gland regulationof endocrine gland regulation  RegulationRegulation ofof endocrine glandendocrine gland activity can be carried out with theactivity can be carried out with the help of four mechanisms:help of four mechanisms: 1.1. NervousNervous ((impulse-mediatorsimpulse-mediators) or) or parahypophysis regulationparahypophysis regulation. With the. With the help of direct nervous influences the activity of following structures ishelp of direct nervous influences the activity of following structures is regulated:regulated:  аа)) adrenal medullaadrenal medulla;;  bb)) neuroendocrineneuroendocrine structuresstructures of hypothalamusof hypothalamus;;  cc)) epiphysisepiphysis.. 2.2. NeuroendocrineNeuroendocrine oror transhypophysartranshypophysar regulationregulation. It is carried out. It is carried out byby neuroendocrine cells of hypothalamusneuroendocrine cells of hypothalamus,, which transformwhich transform nervousnervous impulses in specificimpulses in specific endocrineendocrine process. Along releasing-hormones,process. Along releasing-hormones, which regulate activity of adenohypophysis are synthesized and getwhich regulate activity of adenohypophysis are synthesized and get secretedsecreted in the system of portal vesselsin the system of portal vessels of hypophysisof hypophysis.. 3.3. Endocrine regulationEndocrine regulation. It is that some hormones influence on. It is that some hormones influence on synthesis and other influence secretion of the others. An example ofsynthesis and other influence secretion of the others. An example of this mechanism is the influence of adenohypophysis tropic hormonesthis mechanism is the influence of adenohypophysis tropic hormones on activity of adrenal cortex, thyroid gland, sexual glands.on activity of adrenal cortex, thyroid gland, sexual glands. 4.4. Non-endocrine humoral regulationNon-endocrine humoral regulation is carried out by unspecificis carried out by unspecific humoral factors, in particular by metabolites, ions.humoral factors, in particular by metabolites, ions.
    18. 18.  Pathological processes which are primarity developed in hypothalamusprimarity developed in hypothalamus lead to disorders of transhypophysartranshypophysar and parahypophysarparahypophysar regulation of endocrine glands function.  The activity of hypothalamic centers can be disturbed also secondarilysecondarily in connection with disorders in limbicdisorders in limbic systemsystem (hypocampus, tonsil, olfactory brain) and upper parts of central nervous system which are closely connected with hypothalamus. At that the large role belongs to mental traumamental trauma and other stress influencesstress influences.
    19. 19.  TranshypophysarTranshypophysar regulation includesregulation includes synthesis ofsynthesis of peptidespeptides which arewhich are moving by axonsmoving by axons and reachand reach adenohypophysisadenohypophysis in neurosecretory cellsin neurosecretory cells of mediobasal part of hypothalamus. Here they eitherof mediobasal part of hypothalamus. Here they either stimulate or inhibit formation of tropic hormonesstimulate or inhibit formation of tropic hormones..  Stimulating peptidesStimulating peptides have received the name ofhave received the name of liberins or releasing-factorsliberins or releasing-factors, they are:, they are: thyroliberin, gonadoliberin, somatoliberin etc.thyroliberin, gonadoliberin, somatoliberin etc.  Inhibiting peptidesInhibiting peptides are namedare named statinsstatins –– thyrostatin, somatostatin etc.thyrostatin, somatostatin etc.  Their ratio among themselves is determined formationTheir ratio among themselves is determined formation ofof appropriate tropic hormoneappropriate tropic hormone. Then formation of tropic. Then formation of tropic hormones begins in adenohypophysis –hormones begins in adenohypophysis – somatotropicsomatotropic (STH),(STH), gonadotropicgonadotropic (GTH) etc.(GTH) etc.  Tropic hormonesTropic hormones act on appropriate targets andact on appropriate targets and stimulate derivation of hormones in appropriate glands,stimulate derivation of hormones in appropriate glands, andand STHSTH stimulatesstimulates formation offormation of somatomedinessomatomedines inin tissues – polipeptide hormones,tissues – polipeptide hormones, through which theythrough which they actact..
    20. 20. • By means of parahypophysarparahypophysar mechanism secretory, vessel and trophic influence of CNS on the function of endocrine glands is carried out. • For adrenal medulla, Langerhans’ islets and parathyroid glands it is a major pathway of their regulation. In realization of the function of other glands both pathways of regulation take place. So, the function of thyroid gland is determined not only by TTH, but also by sympathetic impulsation. • The direct irritation of sympathetic nerves increases absorption of iodine by the gland, synthesis of thyroid hormones and their secretion. • Denervation of ovaries causes their atrophy and weakens response on gonadotrophic hormones.
    21. 21.  The disorders ofThe disorders of trans- andtrans- and parahypophysarparahypophysar regulationregulation leads to disfunction of endocrineleads to disfunction of endocrine glands.glands.  The disturbance of one glandThe disturbance of one gland function is calledfunction is called monoglandularmonoglandular process, several glands –process, several glands – pluriglandularpluriglandular process.process.  The disorders of the glandularThe disorders of the glandular function can befunction can be partialpartial, when, when production of only oneproduction of only one hormone is disturbed, orhormone is disturbed, or totaltotal,, when secretion of all hormoneswhen secretion of all hormones is changed.is changed.
    22. 22. Role of mechanisms feedback bondRole of mechanisms feedback bond in endocrine disturbancesin endocrine disturbances • TheThe mechanism of feedbackmechanism of feedback bond is obligated link inbond is obligated link in selfself regulationregulation of glandular activity. The essence of negativeof glandular activity. The essence of negative adverse effects is that formed hormones oppress activity ofadverse effects is that formed hormones oppress activity of structures which carry out the previous stages of regulation.structures which carry out the previous stages of regulation. • Therefore theTherefore the increase of secretionincrease of secretion ofof effectory hormone through certain partseffectory hormone through certain parts causescauses decrease of its formationdecrease of its formation andand entering in bloodentering in blood, and on the contrary, the, and on the contrary, the decreasing of the hormone contentsdecreasing of the hormone contents inin blood causesblood causes increase of intensity of itsincrease of intensity of its formation and secretionformation and secretion. In this way. In this way regulation of cortizol secretion, thyroid andregulation of cortizol secretion, thyroid and sexual hormones is carried out.sexual hormones is carried out. • By the principle of the mechanism ofBy the principle of the mechanism of feedback bond inhibition of the functionfeedback bond inhibition of the function (even atrophy) of the gland during(even atrophy) of the gland during treatment by their or other hormones cantreatment by their or other hormones can occur.occur.
    23. 23. Pathway Example Stimulus Low pH in duodenum S cells of duodenum secrete secretin ( ) Endocrine cell Blood vessel PancreasTarget cells Response Bicarbonate release Negativefeedback – • Hormones are assembled into regulatory pathways • A negative feedback loop inhibits a response by reducing the initial stimulus • Negative feedback regulates many hormonal pathways involved in homeostasis Negative feedback andNegative feedback and antagonistic hormone pairsantagonistic hormone pairs are common features of theare common features of the endocrine systemendocrine system
    24. 24. Control of hormone releaseControl of hormone release 1. Negative feedback ["stimulatory-inhibitory"] 2. Positive feedback ["stimulatory-stimulatory"] 3. Endocrine gland stimuli: humoral stimuli, neural stimuli, hormonal stimuli
    25. 25. Disorders of hormones biosynthesisDisorders of hormones biosynthesis and their secretionand their secretion • Strictly glandular disorders of endocrine functions can be conditioned: 1. By changes of functionally active endocrine cells amount : • a) by decreasedecrease of their amount (removal of gland or its part, damage, necrosis), that results to endocrineendocrine hypofunctionhypofunction; • b) by increaseincrease of their amount (benignt and malignant tumors of glandular epithelium) that is accompanied by features of endocrine hyperfunctionendocrine hyperfunction. 2. Qualitative changes in cells: • a) by disorders of biosynthesis of hormones; • b) by disorders of processes of their secretion.
    26. 26. The main possible reasons of protein-The main possible reasons of protein- peptide hormones synthesis disorders are:peptide hormones synthesis disorders are: • 1) disorders of transcription; • 2) disorders of translation; • 3) deficiency of essential aminoacids; • 4) deficiency of ATP; • 5) disorders of posttranslatory modification and activation.
    27. 27. Disorders of transport, reception and hormones metabolism • The peripheral mechanisms determine activity of hormones excreted into blood, development of peripheral disorders of endocrine functions occurs due to: 1. Disorders of the hormones transport in organism. 2. Disorder of metabolic inactivation of hormones. 3. Disorders of interaction of hormones with peripheral cells - targets. • All hormones is excreted from glands associate with proteins in blood and circulate in two forms – connectedconnected and freefree. From these two forms connected hormone is biologically inactive. The activity is peculiar only to free form of hormone. • The disorders of the hormone transport in an organism can appear in two types of endocrine function disorders: • а) hypofunctionhypofunction – increase of hormone binding and decrease of its contents in the free form; • b) hyperfunctionhyperfunction – decrease of hormone binding and increase in blood of concentration of the free form.
    28. 28. DisorderDisorderss ofof endocrineendocrine functions, connectedfunctions, connected with disturbanceswith disturbances of interaction ofof interaction of hormoneshormones withwith peripheralperipheral cellscells • The influence of hormones on cells - targets is carried out through their action on specific proteins – receptors and is performed in three ways: 1) influences on permeability of biological membranes; 2) stimulation or oppression of enzymes activity; 3) influences on the genetic apparatus of a cell.
    29. 29. This gland makes me wake up in theThis gland makes me wake up in the morning and ready to go!morning and ready to go! Pineal Gland melatonin "The 3rd Eye""The 3rd Eye"
    30. 30. Coordination of Endocrine andCoordination of Endocrine and Nervous Systems in VertebratesNervous Systems in Vertebrates TheThe hypothalamushypothalamus receives information fromreceives information from the nervous system and initiates responsesthe nervous system and initiates responses through the endocrine systemthrough the endocrine system Attached to the hypothalamus is theAttached to the hypothalamus is the pituitarypituitary glandgland composed of the posterior pituitary andcomposed of the posterior pituitary and anterior pituitaryanterior pituitary TheThe posterior pituitaryposterior pituitary stores and secretesstores and secretes hormones that are made in the hypothalamushormones that are made in the hypothalamus TheThe anterior pituitaryanterior pituitary makes and releasesmakes and releases hormones under regulation of thehormones under regulation of the hypothalamushypothalamus
    31. 31. This glandThis gland is called theis called the “master gland”“master gland” because itbecause it secretes ninesecretes nine hormoneshormones many of whichmany of which control othercontrol other endocrineendocrine glands byglands by feedbackfeedback control.control. Pituitary GlandPituitary Gland
    32. 32. Tropic effects only: FSH LH TSH ACTH Nontropic effects only: Prolactin MSH Nontropic and tropic effects: GH
    33. 33. Anterior Pituitary Posterior pituitary Stimulates milk ejection and uterine contractions Ovary and testisOxytocin Conservation of body water KidneyAntidiuretic hormone Control of reproductive function Ovary and testisFollicle stimulating hormone Control of reproductive function Ovary and testisLuteinizing hormone Milk productionMammary glandProlactin Stimulates secretion of glucocorticoids Adrenal gland cortexAdrenocorticotrophic hormone Stimulates secretion of thyroid hormones Thyroid glandThyroid stimulating hormone Promotes growth (indirectly), control of protein, lipid and carbohydrate metabolism Liver, adipose tissueGrowth hormone Major physiologic effects Major target organsHormone
    34. 34. Type ofType of AdenomaAdenoma SecretionSecretion StainingStaining PathologyPathology CorticotrophicCorticotrophic adenomasadenomas SecreteSecrete adrenocotrophicadrenocotrophic hormone (ACTH) andhormone (ACTH) and ProopiomelanocortinProopiomelanocortin (POCM)(POCM) BasophilicBasophilic Cushing’s diseaseCushing’s disease SomatotrophicSomatotrophic adenomasadenomas SecreteSecrete growth hormonegrowth hormone (GH)(GH) AcidophilicAcidophilic AcromegalyAcromegaly (Gigantism)(Gigantism) ThyrotrophicThyrotrophic adenomas (rare)adenomas (rare) SecretSecret thyroid stimulatingthyroid stimulating hormone (TSH)hormone (TSH) BasophilicBasophilic OccasionallyOccasionally hyperthyroidismhyperthyroidism usually does not causeusually does not cause symptomssymptoms GonadotrophicGonadotrophic adenomasadenomas SecreteSecrete luteinizing hormoneluteinizing hormone (LH), follicle stimulating(LH), follicle stimulating hormone (FSH)hormone (FSH) BasophilicBasophilic Usually does notUsually does not cause symptomscause symptoms ProlactinomasProlactinomas SecretSecret prolactinprolactin AcidophilicAcidophilic Galactorrhea,Galactorrhea, hypogonadism,hypogonadism, amenorrhea,amenorrhea, infertility andinfertility and impotenceimpotence Null cellsNull cells adenomasadenomas Do not secrete hormonesDo not secrete hormones May stain positiveMay stain positive for synaptophysinfor synaptophysin
    35. 35. Disturbances of functions of hypophysis. Hypofunction of adenohypophysis (hypopituitaritism) There are panhypopituitarity and partial hypopituitarityThere are panhypopituitarity and partial hypopituitarity
    36. 36. Panhypopituitarity – is the decrease ofPanhypopituitarity – is the decrease of formation of all adenohypophysis hormonesformation of all adenohypophysis hormones • The following clinical forms of panhypopituitarity are known:The following clinical forms of panhypopituitarity are known: 1) Hypophysar cachecsia of SimondsSimonds; 2) Afterbearing necrosis of hypophysis – syndrome of Schegansyndrome of Schegan; 3) Chromophobe hypophysis adenomas, i.e. tumors, which grow from chromophobe cells. For want of it the tumour squeezes and damages glandular cells of adenohypophysis. • The clinical manifestationsclinical manifestations of panhypopituitarity are connected with deficiency of adenohypophysis hormones and disorders of activity of peripheral endocrine glands (thyroid gland, cortex of adrenal, sexual glands). • The first symptomsfirst symptoms of lesion of adenohypophysis occur in damage of 70- 75% of gland tissue, and for development of complete picture of panhypopituitarity destruction of 90-95 % of adenohypophysis is necessary. • Vessels disordersVessels disorders in hypophysis and hypothalamus (most frequently afterbearing longtime spasm of vessels of brain and hypophysis owing of haemorrhage), trauma of the skull basis, tumour of hypophysis and hypothalamus, inflammatory damage (tuberculosis,sepsis) of hypophysis, inherent aplasia and hypoplasia can lead to development of panhypopituitarity. • The most frequently gonadotropic functiongonadotropic function of hypophysis and secretion of STH is damaged with the consequent connection of nonsufficient secretion of ТТH, ACTH and prolactine.
    37. 37. Hypophyseal Simond’s cachexia
    38. 38. Causes of HypopituitarismCauses of Hypopituitarism Tumors and mass lesions — pituitary adenomas, cysts, metastatic cancer, and other lesions Pituitary surgery or radiation Infiltrative lesions and infections — hemochromatosis, lymphocytic hypophysitis Pituitary infarction — infarction of the pituitary gland after substantial blood loss during childbirth (Sheehan’s syndrome) Pituitary apoplexy — sudden hemorrhage into the pituitary gland Genetic diseases — rare congenital defects of one or more pituitary hormones Empty sella syndrome — an enlarged sella turcica that is not entirely filled with pituitary tissue Hypothalamic disorders — tumors and mass lesions (e.g., craniopharyngiomas and metastatic malignancies), hypothalamic radiation, infiltrative lesions (e.g., sarcoidosis), trauma, infections
    39. 39. Partial hypopituitarityPartial hypopituitarity is the disorder of formation of separate hormones of adenohypophysis (not all). The following variants of partial hypopituitarity are described: HypophysarHypophysar nanismnanism 1) Hypophysar nanism (dwarfishnessdwarfishness) - deficiency of STHSTH; 2) Secondary hypohonadism - deficiency of FSH and LHFSH and LH; 3) Secondary hypothyrosisSecondary hypothyrosis - deficiency of TTHTTH; 4) Secondary hypocorticismSecondary hypocorticism - deficiency of ACTHACTH.
    40. 40. • The insufficiency of STHThe insufficiency of STH results to development of hypophysar dwarfishness, or nanism and appears by such disorders: • 1) decrease of intensity of protein synthesisdecrease of intensity of protein synthesis that leads to delay and stop of growth (more than 30% from average) and development of bones, internal organs, muscles. The disorders of protein synthesis in connective tissue results in loss of its elasticity; • 2) decrease of inhibiting action of STHdecrease of inhibiting action of STH on an absorption of glucose with predominance of insulinic effect and development of hypoglycemia; • 3) fallout of fat mobilizingfallout of fat mobilizing action and tendency to obesity.
    41. 41. By producing too much of one or more hormonesBy producing too much of one or more hormones • Adrenocorticotropic hormoneAdrenocorticotropic hormone:: – causes weight gain (particularly in the body’s trunk, notcauses weight gain (particularly in the body’s trunk, not the legs or arms)the legs or arms) – high blood pressurehigh blood pressure – high blood sugarhigh blood sugar – brittle bonesbrittle bones – emotional changesemotional changes – stretch marks on the skinstretch marks on the skin – easy bruising.easy bruising. The insufficiency of ACTH leads to secondary partialThe insufficiency of ACTH leads to secondary partial insufficiency of adrenal cortex.insufficiency of adrenal cortex. The glucocorticoid function suffers mainly.The glucocorticoid function suffers mainly. Mineralocorticoid function practically does not varyMineralocorticoid function practically does not vary
    42. 42.  Insufficiency of TTHInsufficiency of TTH causes secondarycauses secondary decrease function ofdecrease function of thyroid gland andthyroid gland and development ofdevelopment of secondary hypothyrosissecondary hypothyrosis symptoms. As against insymptoms. As against in case of primarycase of primary hypofunction of thyroidhypofunction of thyroid gland the introduction ofgland the introduction of TTH can restore itsTTH can restore its function.function.
    43. 43.  Insufficiency of gonadotropic hormonesInsufficiency of gonadotropic hormones results inresults in decrease of ability of Sertoli cellsdecrease of ability of Sertoli cells toto accumulate androgensaccumulate androgens andand oppression ofoppression of spermatogenesisspermatogenesis andand ability to impregnationability to impregnation in menin men..  In case ofIn case of defect of LGdefect of LG ((LuteinizingLuteinizing)) hormone the function ofhormone the function of Leidig’s cells isLeidig’s cells is infringedinfringed, the formation of androgens ceases, the formation of androgens ceases and develops eunuchoidism withand develops eunuchoidism with preservation of partial ability topreservation of partial ability to impregnation, as the process ofimpregnation, as the process of spermatozoids maturing does not stop.spermatozoids maturing does not stop.
    44. 44. Hyperfunction ofHyperfunction of adenohypophysisadenohypophysis (hyperpituitarism)(hyperpituitarism)  The main reasons ofThe main reasons of hyperpituitarism development arehyperpituitarism development are the benign tumours – adenomas of endocrine cells.the benign tumours – adenomas of endocrine cells.  There areThere are   twotwo groups of adenomasgroups of adenomas..  1.1. Eosinophilic adenomaEosinophilic adenoma, develops from acidophilic cells, develops from acidophilic cells of adenohypophysis forming STH. Clinicallyof adenohypophysis forming STH. Clinically hyperproduction of STH appears byhyperproduction of STH appears by giantismgiantism ((if adenomaif adenoma develops in childrendevelops in children and young people before closing ofand young people before closing of epiphysar cartilages) andepiphysar cartilages) and acromegaliaacromegalia ((in adultin adult).  Giantism).  Giantism is characterized by the proportional increase of all bodyis characterized by the proportional increase of all body components.components.
    45. 45. GigantismGigantism
    46. 46. Jane Bunford 2.41mJane Bunford 2.41m Zeng Jinlian 249 smZeng Jinlian 249 smYao Defen 2.34Yao Defen 2.34
    47. 47. • By producing too much of one or more hormones • Growth hormone: causes ACROMEGALY – a syndrome that includes: • excessive growth of soft tissues and bones • high blood sugar • high blood pressure • heart disease • sleep apnea • excess snoring • carpal tunnel syndrome • pain symptoms (including headache). • Acromegaly appears by increased growth of hands, legs, chin, nose, tongue, liver, kyphoscoliosis. Besides that increased metabolic activity of STH -hyperglycemia, insulin resistanse, even to development of metahypophysar diabetes, fatty infiltration of liver develop.
    48. 48. BITEMPORAL HEMIANOPSIA
    49. 49. Usually the bitemporal hemianopsia isUsually the bitemporal hemianopsia is NOT perfectly symmeetrical. Why?NOT perfectly symmeetrical. Why? Because pituitary tumors are under noBecause pituitary tumors are under no law to grow perfectly midline.law to grow perfectly midline.
    50. 50. • 2. Basophilic adenomaBasophilic adenoma, grows from basophilic cells of adenohypophysis which more often produce ACTH. During this the Itsenko-CushingItsenko-Cushing disease develops. It is characterized by: • а) secondary hypercorticism; • b) strengthened pigmentation of skin. • There are tumors which produce other hormones of adenohypophysis less often: TTH, gonadotropic hormones, prolactin, MSH. • The increased level of ACTH during this disease is combined with increase of level of other products of proopiomelanocortin. BASOPHILIC ADENOMA OF HYPOPHYSISBASOPHILIC ADENOMA OF HYPOPHYSIS
    51. 51. Hyperfunction of neurohypophysisHyperfunction of neurohypophysis • Leads to redundant production vasopressin andLeads to redundant production vasopressin and oxytocin. Their main effects:oxytocin. Their main effects: • VasopressineVasopressine (antidiuretic hormone) renders the following influence through V1 and V2 receptors: 1) Acting on tubulus contortus distalis and collective tubules of kidneys, strengthens reabsorption of water; 2) Causes contraction of smooth muscles of blood vessels; 3) Strengthens glycogenolysis and gluconeogenesis in liver; 4) Stimulates consolidation of memory traces and mobilization of saved information (hormone of memory); 5) Endogenic analgetic (depresses pain).
    52. 52. • OxytocinOxytocin renders the following functional influences: 1) Stimulates secretion of milk (lactation) causing contraction of myoepithelial cells of small-sized ducts of mammary glands; 2) Initiates and strengthens contractions of uterus of pregnant woman; 3) Worsens storing and mobilization of information (amnestic hormone). • Redundant secretion of vasopressin arises in tumors of different tissues forming vasopressin, and also in disorders of hypothalamic endocrine function regulation. Its main manifestation is hypervolemia leading to development of constant arterial hypertension.
    53. 53. GG AA LL AA CC TT OO RR RR HH EE AA
    54. 54. Hypofunction ofHypofunction of neurohypophysisneurohypophysis  Insufficient production of vasopressin results toInsufficient production of vasopressin results to development ofdevelopment of diabetes insipidusdiabetes insipidus.. There are two pathogenetic variants:There are two pathogenetic variants:  central (neurogenic)central (neurogenic) during which will a little quantity ofduring which will a little quantity of vasopressine, is formed andvasopressine, is formed and  nephrogenicnephrogenic duringduring which the sensitivity of epithelialwhich the sensitivity of epithelial cells receptors of distal nephron parts and collectivecells receptors of distal nephron parts and collective tubules to vasopressin action (absence or a little quantitytubules to vasopressin action (absence or a little quantity receptors) is reduced.receptors) is reduced.  TheThe decreasing of water reabsorptiondecreasing of water reabsorption in kidneys resultsin kidneys results toto poliuriapoliuria and decreasing of circulatting blood volumeand decreasing of circulatting blood volume ((hypovolemiahypovolemia),), falling of arterial pressurefalling of arterial pressure andand hypoxiahypoxia..  TheThe decreasing of oxytocindecreasing of oxytocin production appears byproduction appears by disorders of lactation, weakness of labor activitydisorders of lactation, weakness of labor activity..
    55. 55. Adrenal cortex - secretes several classes of steroid hormones (glucocorticoids and mineralocorticoids) - with three concentric zones of cells that differ in the major steroid hormones they secrete. Adrenal medulla - source of the catecholamines epinephrine and norepinephrine. - chromaffin cell is the principle cell type. - The medulla is richly innervated by preganglionic sympathetic fibers and is, in essence, an extension of the sympathetic nervous system.
    56. 56. Effects of mineralocorticoids: Effects of glucocorticoids: 1. Retention of sodium ions and water by kidneys 2. Increased blood volume and blood pressure 2. Possible suppression of immune system 1. Proteins and fats broken down and converted to glucose, leading to increased blood glucose Adrenal gland Kidney Adrenal cortex Adrenal cortex Glucocorticoids – glucose from noncarb sources, such as muscles Mineralocorticoids (aldosterone) – induces kidneys to reabsorb water and salts Both of these deal with long-term stress
    57. 57. Actions of CortisolActions of Cortisol Major InfluenceMajor Influence Effect on BodyEffect on Body Glucose metabolismGlucose metabolism Stimulates gluconeogenesisStimulates gluconeogenesis Decreases glucose use by the tissuesDecreases glucose use by the tissues Protein metabolismProtein metabolism Increases breakdown of proteinsIncreases breakdown of proteins Increases plasma protein levelsIncreases plasma protein levels Fat metabolismFat metabolism Increases mobilization of fatty acidsIncreases mobilization of fatty acids Increases use of fatty acidsIncreases use of fatty acids Anti-inflammatory actionAnti-inflammatory action (pharmacologic levels)(pharmacologic levels) Stabilizes lysosomal membranes of the inflammatory cells, preventingStabilizes lysosomal membranes of the inflammatory cells, preventing the release of inflammatory mediatorsthe release of inflammatory mediators Decreases capillary permeability to prevent inflammatory edemaDecreases capillary permeability to prevent inflammatory edema Depresses phagocytosis by white blood cells to reduce the release ofDepresses phagocytosis by white blood cells to reduce the release of inflammatory mediatorsinflammatory mediators Suppresses the immune responseSuppresses the immune response • Causes atrophy of lymphoid tissueCauses atrophy of lymphoid tissue • Decreases eosinophilsDecreases eosinophils • Decreases antibody formationDecreases antibody formation • Decreases the development of cell-mediated immunityDecreases the development of cell-mediated immunity Reduces feverReduces fever Inhibits fibroblast activityInhibits fibroblast activity Psychic effectPsychic effect May contribute to emotional instabilityMay contribute to emotional instability Permissive effectPermissive effect Facilitates the response of the tissues to humoral and neural influences,Facilitates the response of the tissues to humoral and neural influences, such as that of the catecholamines, during trauma and extreme stresssuch as that of the catecholamines, during trauma and extreme stress
    58. 58. Disorders of adrenal gland functionDisorders of adrenal gland function  The most frequently there are followingThe most frequently there are following manifestations:manifestations: 1)1) HypofunctionHypofunction of adrenal cortex - hypocorticismof adrenal cortex - hypocorticism Addison diseaseAddison disease ;; 2)2) HyperfunctionHyperfunction of fascicular zone - syndrome ofof fascicular zone - syndrome of Itsenko-CushingItsenko-Cushing –– Hypersecretion of cortisolHypersecretion of cortisol;; 3)3) HyperfunctionHyperfunction of glomerulose zone –of glomerulose zone – hyperaldosteronism –hyperaldosteronism – Hyperfunction of adrenalHyperfunction of adrenal cortex resulting in excess secretion of aldosteronecortex resulting in excess secretion of aldosterone;; 4)4) DysfunctionDysfunction of adrenal cortex - adrenogenitalof adrenal cortex - adrenogenital syndromesyndrome
    59. 59. Insufficiency of adrenal cortex • According to etiology there are primary and secondary kinds of adrenal cortex insufficiency. • Primary insufficiencyPrimary insufficiency arises as a result of adrenals injury, • secondarysecondary is connected with the defeat of hypotalamus (deficiency of corticoliberin), or with hypofunction of adenohypophysis (deficiency of ACTH). • Insufficiency of corticosteroids can be totaltotal when the operation of all hormones drops out, and partialpartial fallout of activity of one adrenal hormone. • Insufficiency of adrenal cortex can be acuteacute and chronicchronic. • Examples ofExamples of acute insufficiencyacute insufficiency areare: а) state after removal of adrenals; b) hemorrhage in adrenals which arises during sepsis, meningococci infection (syndrome Waterhouse-Friderixan); c) syndrome of cancellation of glucocorticoides preparations. • Fast falling of the adrenals function causes development of collaps and the patients can die during the first day.
    60. 60. • TheThe chronic insufficiencychronic insufficiency ofof adrenals cortex is characterized foradrenals cortex is characterized for Adison’s diseaseAdison’s disease (bronzed disease).(bronzed disease). • The most often reasons of it are:The most often reasons of it are: а) tuberculose destruction of adrenals; b) autoimmune process. Tuberculose of adrenal gland. Adison’s disease
    61. 61. Skin hyperpigmentation at case of Adison’s disease
    62. 62. ІІ. Manifestation, connected with the falling of. Manifestation, connected with the falling of mineralocorticoids functions of adrenal cortex:mineralocorticoids functions of adrenal cortex: • 1) dehydration develops owing to loss of sodium ionsloss of sodium ions (decreases rearbsortion) with the loss of water (poliuria); • 2) arterial hypotension is stipulated by decrease of circulating blood volume; • 3) hemoconcentration (condensation of blood) is connected with liquid loss, results to disorders of microcirculation and hypoxiadisorders of microcirculation and hypoxia; • 4) decreasing of kidney blood circulation is stipulated by increase of arterial pressure with disturbances of glomerulardisturbances of glomerular filtrationfiltration and development of intoxicationintoxication (nitrogenemia); • 5) hyperpotassiumemia is stipulated by decrease of canalesdecrease of canales secretion of potassium ionssecretion of potassium ions and their output from the damaged cells. It causes disorders of function of arousing tissues; • 6) distal canales acidosis. It is connected with disorders ofdisorders of acidogenesisacidogenesis in distal nephron canales; • 7) gastro-intestinal disorders (nausea, vomiting, diarrhea). Loss of sodium (osmotic diarrhea) and intoxication have significant meaning. This disorders without appropriate correction result to death.
    63. 63. ІІІІ. Manifestations stipulated by disorders of. Manifestations stipulated by disorders of glucocorticoid function of adrenals. To suchglucocorticoid function of adrenals. To such manifestations concern:manifestations concern: • 1) hypoglycemia which results to starvation; • 2) arterial hypotension (permissive reaction on catecholamines); • 3) decrease reaction of fat tissue on lipotrophic stimules; • 4) decrease resistance of an organism on action of different pathogenic factors; • 5) decrease of ability to remove water during water load (water poisoning); • 6) muscular weakness and fast tiredness; • 7) emotional disorders (depression); • 8) delay of growth and development of children; • 9) sensor disorders - loss of ability to distinguish separate shades gustatory osmotic acoustical sensations; • 10) distress-syndrome of a newborn (hyalinic membranosis). It is stipulated by disorders of surfactant formation in lungs owing to what lungs are not straightened after birth of a child.
    64. 64. Increase of adrenals cortex functionIncrease of adrenals cortex function • HyperaldosteronismHyperaldosteronism.. Arises during hyperfunction of glomerular zone of adrenals cortex, which produce mineralcorticoides. There are primaryprimary and secondary hyperaldosteronismsecondary hyperaldosteronism. • Primary hyperaldosteronismPrimary hyperaldosteronism (Conn syndromeConn syndrome) arises in adenoma of zone glomerular, which secretes high quantity of aldosteron. Main manifestations of this disease: 1) arterial hypertension. It is connected with increase of sodium contents in blood and in wall of blood vessels, after what the sensitivity of their smooth muscles to action of pressore factors, particularly catecholamines increases. 2) hypopotassiumaemia (result of hypersecretion of potassium ions in canaliculas of kidneys). It causes disorders of arousing organs and tissues (disorders of heart activity, miostenia, pareses); 3) ungas alcalosis. It is connected with amplification of acidogenesis in distall nephron canaliculas; 4) polyuria arises as a consequence sensitivity of kineys canales epithelium loss to action of vasopressin. It explains absence of volume increase of circulatting blood and edema. • Secondary hyperaldosteronismSecondary hyperaldosteronism is a result of renin-angiotensin system activation. This state appears by: a) arterial hypertension; b) edemas; c) hypopotassiumaemia; d) ungas alcalosis.
    65. 65. • There are two clinical forms of hypercorticism with hyperproduction of glucocorticoides: 1. Cushing’s diseaseCushing’s disease – basophil adenoma of anterior hypophysis part. 2. Cushing’s syndromeCushing’s syndrome: • а) tumoral – adenoma of zona fasticulata of adrenal cortex; • b) ectopic production of АCТH by some malignant tumors (pulmonar cancer); • c) iatrogenic – introduction of glucocorticoides in an organism with the medical purpose.
    66. 66. MOON FACIES BUFFALO HUMP STRIAE
    67. 67. GlucocorticoidGlucocorticoid hypercorticism appears by:hypercorticism appears by: 1) arterial hypertension; 2) hyperglycaemia – metasteroid diabetes mellitus; 3) obesity; 4) development of infectious diseases without signs of an inflammation; 5) gastric hypersecretion and formation of ulcers in stomach and duodenum; 6) osteoporosis; 7) muscular weakness; 8) slow of wounds healing.
    68. 68. • Adrenogenital syndromeAdrenogenital syndrome results from the hereditary stipulated blockade of cortisole synthesis and amplified formation of androgens from general intermediate products. • Depending on the level of blockade of cortisole synthesis there are three variants of adrogenital syndrome. • І. Disorders of early stages of synthesis – deficiency of glucocorticoides, mineralcorticoides and androgens hyperproduction. Manifestations: signs of insufficiency of gluco- and mineralocorticoidal functions of adrenal cortex features of early sexual maturing in males, virilization in women (appearance of man's sexual features). • ІІ. Disorders of intermediate stages – deficiency of glucocorticoides, surplus of androgens, formation of mineralocorticoides is not infringed (classical androgenic syndrome). Manifestations are the same, as in the first case, only without signs of insufficiency of mineralocorticoidal function. • ІІІ. Disorders at final stages of cortirol synthesis – deficiency of glucocorticoides, hyperproduction of androgens and mineralocorticoide. Features of hyperaldosteronism are connected with manifestations of classical androgenital syndrome. AdrenogenitalAdrenogenital syndromesyndrome
    69. 69. Disorders of adrenal medulla functionDisorders of adrenal medulla function  Hypofunction of adrenal medullaHypofunction of adrenal medulla  happens happens seldom because of the fact that these functionsseldom because of the fact that these functions can be accepted by other chromaphine cell.can be accepted by other chromaphine cell.  Hyperfunction of adrenal medullaHyperfunction of adrenal medulla  arises arises during tumors of chromaphine cells –during tumors of chromaphine cells – pheochromocytome. Appears by arterialpheochromocytome. Appears by arterial hypertension, tachycardia, extrasystole, flateringhypertension, tachycardia, extrasystole, flatering of atriums, hyperglycaemia, hyperlipidaemia,of atriums, hyperglycaemia, hyperlipidaemia, hyperthermia. Development of moderatelyhyperthermia. Development of moderately expressed diabetus, thyreotoxicosis is possible. Inexpressed diabetus, thyreotoxicosis is possible. In time of paroxizm vertigo, headache,time of paroxizm vertigo, headache, hallucinations, increased excitability of thehallucinations, increased excitability of the nervous system, cramps appear.nervous system, cramps appear.
    70. 70. HYPOADRENALISMHYPOADRENALISM Caused by any anatomic or metabolic lesion of the adrenalCaused by any anatomic or metabolic lesion of the adrenal cortex that impairs output of the cortical steroids.cortex that impairs output of the cortical steroids. Primary Acute Adrenal InsufficiencyPrimary Acute Adrenal Insufficiency -- Waterhouse Friderichsen SyndromeWaterhouse Friderichsen Syndrome due to overwhelming septicemic infection caused bydue to overwhelming septicemic infection caused by meningococci, but occasionally other virulentmeningococci, but occasionally other virulent organism such as gonococci,pneumococi andorganism such as gonococci,pneumococi and staphylococci.staphylococci. morphology: massive bilateral adrenal hemorrhagemorphology: massive bilateral adrenal hemorrhage
    71. 71. ADRENAL MEDULLAADRENAL MEDULLA PHEOCHROMOCYTOMA:PHEOCHROMOCYTOMA: - associated with catecholamine- Induced hypertension. - occassionally, this tumor produces other biogenic steroids or peptides associated with Cushing’s Syndrome. -morphology: - ave . weight of 100 gms - Zellballen appearance
    72. 72.  This large adrenal neoplasmThis large adrenal neoplasm has been sectioned in half.has been sectioned in half. Note the grey-tan color of theNote the grey-tan color of the tumor compared to the yellowtumor compared to the yellow cortex stretched around it andcortex stretched around it and a small remnant of remaininga small remnant of remaining adrenal at the lower right.adrenal at the lower right. This patient had episodicThis patient had episodic hypertension. This is a tumorhypertension. This is a tumor arising in the adrenal medullaarising in the adrenal medulla - a- a pheochromocytomapheochromocytoma.. T N
    73. 73.  Cardiovascular:Cardiovascular: Coronary arteryCoronary artery disease, hypertension, stroke, arrhythmia.disease, hypertension, stroke, arrhythmia.  Muscles:Muscles: Tension headaches, backacheTension headaches, backache  Connective tissues:Connective tissues: Rheumatoid arthritisRheumatoid arthritis  Pulmonary:Pulmonary: Asthma.Asthma.  Immune:Immune: Immunosuppression, deficiency,Immunosuppression, deficiency, autoimmunityautoimmunity  Gastrointestinal:Gastrointestinal: Ulcer, irritable bowelUlcer, irritable bowel syndrome, diarrhea, nausea and vomiting,syndrome, diarrhea, nausea and vomiting, ulcerative colitisulcerative colitis  Integumetary:Integumetary: Eczema, neurodermatitis,Eczema, neurodermatitis, acneacne  Endocrine:Endocrine: Diabetes mellitus, amenorrheaDiabetes mellitus, amenorrhea  Central nervous:Central nervous: Fatigue and lethargy, type AFatigue and lethargy, type A behavior, overeating, depression, insomnia.behavior, overeating, depression, insomnia.
    74. 74. Literature:Literature: 1.1. General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin –General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin – Vinnytsia: Nova Knuha Publishers – 2011. – P.Vinnytsia: Nova Knuha Publishers – 2011. – P. 588588––612612.. 2.2. Gozhenko A.I. General and clinical pathophysiology / A.I. Gozhenko, I.P.Gozhenko A.I. General and clinical pathophysiology / A.I. Gozhenko, I.P. Gurcalova // Study guide for medical students and practitioners. Edited byGurcalova // Study guide for medical students and practitioners. Edited by prof.Zaporozan, OSMU. – Odessa. – 2005.– P. 271–282.prof.Zaporozan, OSMU. – Odessa. – 2005.– P. 271–282. 3.3. Essentials of Pathophysiology: Concepts of Altered Health States (LippincottEssentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams & Wilkins), Trade paperback. – 2003Williams & Wilkins), Trade paperback. – 2003 // Carol Mattson Porth, Kathryn J.Carol Mattson Porth, Kathryn J. Gaspard. – Chapter 30, 31. – P. 529–545.Gaspard. – Chapter 30, 31. – P. 529–545. 4.4. Symeonova N.K. Pathophysiology / N.K. Symeonova // Kyiv, AUS medicineSymeonova N.K. Pathophysiology / N.K. Symeonova // Kyiv, AUS medicine Publishing. – 2010. – P. 484–493, 506–512.Publishing. – 2010. – P. 484–493, 506–512. 5.5. Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme.Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme. Stuttgart. New York. – 2000. – P. 256–271.Stuttgart. New York. – 2000. – P. 256–271. 6.6. Corwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3thCorwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3th edition. Copyright Вedition. Copyright В.. – Lippincott Williams & Wilkins – 2008. –– Lippincott Williams & Wilkins – 2008. – Chapter 9. – P.Chapter 9. – P. 245– 249, 251–255, 260–264, 267–274, 277–279.245– 249, 251–255, 260–264, 267–274, 277–279. 7.7. Robbins and Cotran Pathologic Basis of Disease 8th edition./ Kumar, Abbas,Robbins and Cotran Pathologic Basis of Disease 8th edition./ Kumar, Abbas, Fauto. – 2007. – ChapterFauto. – 2007. – Chapter 2020. – P.. – P. 751–757, 789–801751–757, 789–801.. 8.8. Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L.Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasik // Elsevier Inc, 4th edition. – 2010. – P. 904–914, 920–926, 931–936.Banasik // Elsevier Inc, 4th edition. – 2010. – P. 904–914, 920–926, 931–936. 9.9. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, GlennPathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin. – New York, Milwaukee. – 2009. – P. 1008–1030.Matfin. – New York, Milwaukee. – 2009. – P. 1008–1030.
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